Submissions for variant NM_004403.3(GSDME):c.119dup (p.Lys41fs)

dbSNP: rs758488919

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214538	SCV000271627	uncertain significance	not specified	2015-11-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Lys41fs varia nt in DFNA5 has not been previously reported in individuals with hearing loss, b ut has been identified in 0.21% (137/66836) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs758488919 ). This variant is predicted to cause a frameshift, which alters the protein?s a mino acid sequence beginning at position 41 and leads to a premature termination codon 113 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. However, only variants resulting in altered splic ing and skipping of exon 8 have been reported to be causative for hearing loss t hrough a gain of function mechanism of disease (Van Laer 2004). The p.Lys41fs va riant is located in exon 2 of DFNA5 and is expected to result in loss of functio n (LoF), which is not a known mechanism of hearing loss in this gene. In fact, a frameshift variant in DFNA5 has been reported in members of an Iranian family, in which the variant did not segregate with the hearing loss (Van Laer 2007). In summary, while the clinical significance of the p.Lys41fs variant is uncertain, its frequency in the general population and the lack of evidence supporting a L oF mechanism for hearing loss in DFNA5 suggests it is more likely to be benign.
GeneDx	RCV000963202	SCV000710432	likely benign	not provided	2022-03-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000963202	SCV001110341	likely benign	not provided	2025-01-23	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001544543	SCV001763589	benign	Nonsyndromic genetic hearing loss	2021-07-15	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The filter allele frequency of c.119dupA in DFNA5 gene is 2.9% (330/10368 with 95%CI) in Ashkenazi Jewish population in gnomad database, exceeding the treshold for autosomal dominant non-syndromic hearing loss stablished by the Hearing Loss Expert Panel group, meeting BA1. Although c.119dup is a frameshift variant (p.Lys41Glufs*113), it was reported that DFNA5-associated hearing loss is caused by a gain-of-function and not haplo-insufficiency (PMID:15173223, 7427029). Therefore PVS1 is not applied. In this report, c.119dupA was a confirmed de novo occurence identified in a sporadic congenital moderate non-syndromic hearing loss patient, meeting PS2. Considering BA1 and PS2, the variant is classifie as Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000963202	SCV004163845	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	GSDME: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003937850	SCV004753854	benign	GSDME-related disorder	2020-03-12	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).