Submissions for variant NM_001038603.3(MARVELD2):c.1331+1G>A

gnomAD frequency: 0.00001  dbSNP: rs762352115

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214632	SCV000271393	pathogenic	Rare genetic deafness	2017-05-16	criteria provided, single submitter	clinical testing	The c.1331+1G>A variant in MARVELD2 has been reported as a homozygous variant in 4 individuals with nonsyndromic hearing loss from one family (Chishti 2008). It has also been identified in 1/111500 European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762352115). Alt hough this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency for recessive hearing loss. Th is variant occurs in the invariant region (+/-1,2) of the splice consensus seque nce and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MARVELD2 gene is an established disease mechani sm in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on hom ozygosity in affected individuals, segregation evidence, predicted impact on spl icing and encoded protein, and extremely low allele frequency in the general pop ulation.
DASA	RCV000001258	SCV002073778	pathogenic	Autosomal recessive nonsyndromic hearing loss 49	2022-02-05	criteria provided, single submitter	clinical testing	The c.1331+1G>A variant is located in a canonical splice-site, and it is predicted to alter gene function due to either exon skipping or nonsense-mediate decay – NMD, and the variant is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 228359; PMID: 25788563 ) - PS4_supporting. The variant is present at low allele frequencies population databases (rs762352115 – gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
OMIM	RCV000001258	SCV000021408	pathogenic	Autosomal recessive nonsyndromic hearing loss 49	2008-01-01	no assertion criteria provided	literature only
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000001258	SCV000902328	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 49	2019-02-26	no assertion criteria provided	case-control