Submissions for variant NM_001127453.2(GSDME):c.991-21TTC[2]

dbSNP: rs727505273

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156800	SCV000206521	pathogenic	Rare genetic deafness	2014-10-03	criteria provided, single submitter	clinical testing	c.991-21TTC[2] (DFNA5; NM_004403.2; Chr7g.24746008_24746010delGAA; GRCh37): The c.991-21TTC[2] variant in DFNA5 has been reported in 4 Asian individuals with no n-syndromic sensorineural hearing loss, segregated with disease in 27 affected r elatives from 3 families and was absent in 440 Asian control chromosomes (Yu 200 3, Park 2010, Nisho 2014). It has also been previously identified by our laborat ory in one individual with hearing loss. This variant is a deletion of one unit of a trinucleotide (TTC) repeat sequence normally present as a triplicate (3 rep eat units), resulting in two copies of the TTC repeat. This variant is located i n the 3' splice region and has been shown to cause aberrant splicing, by skippin g of exon 8 (Yu 2003), which is predicted to lead to an abnormal or absent prote in. Several other variants in DFNA5 that have been reported to cause hearing los s are located in introns 7 or 8 and are expected to cause exon 8 skipping (Bisch off 2004, Van Laer 2005, Cheng 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the pr evious reports in affected individuals, segregations, and absence in controls.
CeGaT Center for Human Genetics Tuebingen	RCV001092560	SCV001249116	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001092560	SCV001768211	pathogenic	not provided	2025-02-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate adjacent exon 8 skipping and describe a hypothesized dominant-negative mechanism (PMID: 14559215); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24506266, 34956325, 14676472, 9771715, 17868390, 29266521, 29849037, 32486382, 32747562, 36350814, 35982127, 38297846, 38400873, 39066985, 14559215, 19911014)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001092560	SCV001905592	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001808425	SCV002059892	pathogenic	Autosomal dominant nonsyndromic hearing loss 5	2020-08-01	criteria provided, single submitter	research	Analysis of patient-derived RNA indicates that DFNA5/GSDME c.991-15_991-13delTTC weakens exon 8 splice acceptor, leading to loss of exon 8 in message and stop at codon 372 (Abu Rayyan 2020). The variant is heterozygous in 5 Palestinian children with progressive hearing loss, with average age at onset of 17 years. It is absent from 1300 Palestinian controls and from gnomAD v2.1.1.
3billion, Medical Genetics	RCV001808425	SCV002318560	pathogenic	Autosomal dominant nonsyndromic hearing loss 5	2022-03-22	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24506266, 19911014, 14559215) and reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 19911014, 14559215). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000179997, PMID:14559215). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000041). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV001808425	SCV003826981	pathogenic	Autosomal dominant nonsyndromic hearing loss 5	2022-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092560	SCV004294458	pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the DFNA5 gene. It does not directly change the encoded amino acid sequence of the DFNA5 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with non-syndromic deafness (PMID: 14559215, 29266521). It has also been observed to segregate with disease in related individuals. Studies have shown that this variant results in skipping of exon 8 and introduces a new termination codon (PMID: 14559215). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001808425	SCV005416637	pathogenic	Autosomal dominant nonsyndromic hearing loss 5		criteria provided, single submitter	clinical testing	PM2_Supporting+PP1_Strong+PS4_Moderate+PS3
OMIM	RCV001808425	SCV000022330	pathogenic	Autosomal dominant nonsyndromic hearing loss 5	2010-01-01	no assertion criteria provided	literature only
Diagnostics Centre, Carl Von Ossietzky University Oldenburg	RCV001808425	SCV005049566	pathogenic	Autosomal dominant nonsyndromic hearing loss 5	2023-10-24	no assertion criteria provided	clinical testing	The GSDME:c.991-15_991-13delTTC splice variant is located 13 nucleotides upstream of exon 7 of the GSDME gene. This variant is classified as very rare in the overall population (allele frequency in gnomAD, v4.1.0= 0.000004114). The variant has been consistently classified as Pathogenic in nine entries in ClinVar (ClinVarID: 179997). The variant has been reported in several affected individuals with sensorineural with hearing loss and to co-segregate with the disease (PMID: 24506266, 19911014, 14559215). Experimental data suggest that the variant leads to skipping of exon 8 and thus to a non-functional protein (PMID: 14559215). In summary, this variant is classified as Pathogenic.