Upgrading an intronic TMEM67 variant of unknown significance to likely pathogenic through RNA studies and community data sharing

Abstract

Fetal phenotype: A couple of Ashkenazi Jewish descent was referred for an early anatomy scan at 14 + 2 weeks of gestation following a previous pregnancy termination due to posterior encephalocele and enlarged kidneys. The index pregnancy was also positive for several fetal abnormalities, including enlarged kidneys with cystic dysplasia and abnormal cerebellar morphology highly suggestive of Joubert syndrome.Genetic diagnostic test performed, result, and interpretation: Trio exome sequencing revealed compound heterozygosity for variants in the TMEM67 gene: a known pathogenic maternally inherited variant found in trans with a paternal intronic variant of unknown significance. RNA analysis revealed that the intronic variant creates a cryptic acceptor splice site in intron 12, leading to the insertion of 22 bp and causing a frameshift with a premature stop codon. This analysis enabled the reclassification of the intronic variant to likely pathogenic. Implications and novelty:This information empowered the couple to make informed reproductive choices and opt for preimplantation genetic testing (PGT) for future pregnancies. Key pointsWhat's already known about this topic? � Intronic variants are often classified as variants of unclear significance (VUS). What does this study add?� This report highlights the importance of RNA analysis in cases where an intronic VUS is found in trans with a pathogenic or likely pathogenic variant in an autosomal recessive gene compatible with the fetal phenotype.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

“…Over the past years, we have witnessed near continuous revolution in terms of the standards and rules governing how to weigh and combine evidence with a view to improving our classification of variants, as reflected by the abovementioned works that have attempted to adapt or refine the ACMG/AMP guidelines [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Directly or indirectly related to these adaptations or refinements, variant reclassifications (either upgrades or downgrades) have been a frequent occurrence in the literature (e.g., see recent reports [108][109][110][111][112][113][114][115][116][117][118]. It is our hope that our proposed general variant classification framework will stimulate discussion and debate and lead to further improvements in variant classification.…”

Facilitating variant curation sharing for fetal precision genomics: A new venture for prenatal diagnosis

“…We will consider publishing variants of uncertain significance (VUS) if they are a very close fit to the phenotype and need minimal additional evidence to allow conferring of P/LP status. The format of these short papers, designated as Fetal Phenotype‐Genotype Report , are illustrated in the reports by Kurolap 10 and Horton‐Bell 11 and their colleagues published in this issue. Instructions can be found in the instructions for authors (https://obgyn.onlinelibrary.wiley.com/hub/journal/10970223/about/author-guidelines).…”