Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Oza, Andrea M.; DiStefano, Marina T.; Hemphill, Sarah E.; Cushman, Brandon J.; Grant, Andrew R.; Siegert, Rebecca K.; Shen, Jun; Chapin, Alex; Boczek, Nicole J.; Schimmenti, Lisa A.; Murry, Jaclyn B.; Hasadsri, Linda; Nara, Kiyomitsu; Kenna, Margaret A.; Booth, Kevin T.; Azaiez, Héla; Griffith, Andrew J.; Avraham, Karen B.; Kremer, Hannie; Rehm, Heidi L.; Amr, Sami S.; Tayoun, Ahmad N. Abou

doi:10.1101/313734

Cited by 39 publications

(62 citation statements)

References 97 publications

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“…Enlis Genome Research (https://www.enlis.com/) software was utilized for filtering of variants. The variants were initially filtered according to autosomal dominant inheritance model by using gnomAD (https://gnomad.broadinstitute.org/), 1000 genomes (http://www.internationalgenome.org/), and dbSNP 151 (https://www.ncbi.nlm.nih.gov/snp) databases with minor allele frequency of less than 0.0002 as suggested . Variants were also filtered for the presence in less than two families in our internal database that includes >3000 exomes.…”

Section: Methodsmentioning

confidence: 99%

“…Co‐segregating variants with HL were subsequently ranked based on conservation of the mutated nucleotide with a GERP score > 2, and in silico prediction tools with a REVEL score ≥ 0.7 and CADD score > 20 . American College of Medical Genetics (ACMG) guidelines and ClinGen Hearing Loss Gene Curation Expert Panel suggestions were considered for variant interpretation . Subsequently, all variants located in previously reported deafness genes (hereditary hearing loss homepage; https://hereditaryhearingloss.org/) were investigated for segregation.…”

Section: Methodsmentioning

confidence: 99%

“…org/), and dbSNP 151 (https://www.ncbi.nlm.nih.gov/snp) databases with minor allele frequency of less than 0.0002 as suggested. 11 Variants were also filtered for the presence in less than two families in our internal database that includes >3000 exomes. Sanger sequencing was used to confirm and evaluate co-segregation of the variants including individual II:5, who did not have sufficient amount of DNA for exome sequencing.…”

Section: Whole-exome Sequencing and Variant Filteringmentioning

confidence: 99%

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Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss

et al. 2019

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Auditory reception relies on the perception of mechanical stimuli by stereocilia and its conversion to electrochemical signal. Mechanosensory stereocilia are abundant in actin, which provides them with structural conformity necessary for perception of auditory stimuli. Out of three major classes of actin‐bundling proteins, plastin 1 encoded by PLS1, is highly expressed in stereocilia and is necessary for their regular maintenance. A missense PLS1 variant associated with autosomal dominant hearing loss (HL) in a small family has recently been reported. Here, we present another PLS1 missense variant, c.805G > A (p.E269K), in a Turkish family with autosomal dominant non‐syndromic HL confirming the causative role of PLS1 mutations in HL. We propose that HL due to the p.E269K variant is from the loss of a stable PLS1‐ACTB interaction.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Whole-exome Sequencing and Variant Filteringmentioning

confidence: 99%

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Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss

et al. 2019

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“…The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines are commonly used to provide standard germline‐variant classifications (Richards et al, 2015). These guidelines were originally designed to be used for any Mendelian disease gene, but in an effort to improve and standardize classification strategies, they have also been further specified to individual genes of interest by ClinGen expert panel groups, including PTEN (Mester et al, 2018), CDH1 (Lee et al, 2018), PAH (Zastrow et al, 2018), hearing loss genes (Oza et al, 2018), RASopathy genes (Gelb et al, 2018), MYH7 (Kelly et al, 2018), and TP53 (https://clinicalgenome.org/site/assets/files/3876/clingen_tp53_acmg_specifications_v1.pdf, manuscript in preparation). This involves determining which forms of data are most informative for a specific gene and the corresponding phenotype and may include considering disease penetrance and prevalence to establish frequency cutoffs, assessing the relevance of functional assays, and in some cases, modifying the weight assigned to an ACMG/AMP code depending its relevance to the gene–disease relationship in question.…”

Section: Introductionmentioning

confidence: 99%

Differences in patient ascertainment affect the use of gene‐specified ACMG/AMP phenotype‐related variant classification criteria: Evidence for TP53

et al. 2020

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The American College of Medical Genetics and Genomics/Association for MolecularPathology (ACMG/AMP) guidelines for variant classification are widely used for clinical interpretation of gene test results. These guidelines may be specified to genes/ syndromes of interest to improve their utility in the clinical setting. As part of these specifications, phenotype-related criteria can be detailed and weighted depending on the personal history of disease for a given variant carrier. We investigated how ascertainment can affect the significance and/or weight of patient phenotype as a predictor of germline-variant pathogenicity, using the Li-Fraumeni Syndrome gene TP53 as an example. Likelihood ratios in favor of variant pathogenicity were determined for a report of the personal history of several TP53-related cancers, using data from 2,656 probands undergoing single-gene testing (SGT) and 15,483 undergoing multi-gene panel testing (MGPT). Overall, TP53-associated cancers were more predictive of pathogenicity, and demonstrated greater evidence weight, in the MGPT versus SGT dataset. This observation is almost certainly explained by differences in proband ascertainment for the two streams of testing, and these findings have implications for germline-variant classification using ACMG/AMP guidelines. K E Y W O R D SACMG, ascertainment, TP53, variant classification, VCEP

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“…The physical assessments and medical evaluations confirmed the PDO due to the novel identified variant in this family. According to the American College of Medical Genetics and Genomics‐the Association for Molecular Pathology (ACMG‐AMP) variant interpretation guidelines (Biesecker & Harrison, ; Oza et al, ), this variant could be classified as a likely pathogenic variant, albeit functional studies to further confirm the pathogenicity of the variant in appropriate animal models will be recommended.…”

Section: Introductionmentioning

confidence: 99%

Whole‐exome sequencing identified a novel variant in an Iranian patient affected by pycnodysostosis

Razmara

Azimi²,

Bitaraf

et al. 2020

Molec Gen & Gen Med

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Background Whole‐exome sequencing (WES) has emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. In this study, we aimed to find the potential genetic cause of skeletal disease, a heterogeneous disease, revealing the obvious short stature phenotype. In an Iranian family, we used solo‐WES in a suspected patient to decipher the potential genetic cause(s). Methods A comprehensive clinical and genotyping examination was applied to suspect the disease of the patient. The solo clinical WES was exploited, and the derived data were filtered according to the standard pipelines. In order to validate the WES finding, the region harboring the candidate variant in the CTSK gene was amplified from genomic DNA and sequenced directly by Sanger sequencing. Results Sequence analysis revealed a rare novel nonsense variant, p.(Trp320*); c.905G>A, in the CTSK gene (). In silico analysis shed light on the contribution of the variant to the pathogenicity of pycnodysostosis. This variant was confirmed by Sanger sequencing and further clinical examinations of the patient confirmed the disease. Conclusion The present study shows a rare variant of the CTSK gene, which inherited as autosomal recessive, in an Iranian male patient with pycnodysostosis. Taken together, the novel nonsense CTSK variant meets the criteria of being likely pathogenic according to the American College of Medical Genetics and Genomics‐the Association for Molecular Pathology (ACMG‐AMP) variant interpretation guidelines.

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Expert Specification of the ACMG/AMP Variant Interpretation Guidelines for Genetic Hearing Loss

Cited by 39 publications

References 97 publications

Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss

Novel variant p.E269K confirms causative role of PLS1 mutations in autosomal dominant hearing loss

Differences in patient ascertainment affect the use of gene‐specified ACMG/AMP phenotype‐related variant classification criteria: Evidence for TP53

Whole‐exome sequencing identified a novel variant in an Iranian patient affected by pycnodysostosis

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