Submissions for variant NM_016239.4(MYO15A):c.6764+2T>A

gnomAD frequency: 0.00009  dbSNP: rs763975867

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000369680	SCV000343564	likely pathogenic	not provided	2016-07-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000600824	SCV000731575	likely pathogenic	Rare genetic deafness	2019-01-04	criteria provided, single submitter	clinical testing	The c.6764+2T>A variant in MYO15A has been reported in 3 individuals with hearin g loss (Neveling 2013, LMM data). However, only one of these individuals carried a second variant in MYO15A (Neveling 2013). The c.6764+2T>A variant has also be en identified in 0.0079% (6/75702) of European chromosomes by gnomAD (http://gno mad.broadinstitute.org). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. This variant occurs in the invariant region (+/- 1,2) of the splice con sensus sequence and is predicted to cause altered splicing leading to an abnorma l or absent protein. Loss of MYO15A function is an established disease mechanism in autosomal recessive hearing loss. In summary, although additional studies ar e required to fully establish its clinical significance, the c.6764+2T>A variant meets criteria to be classified as likely pathogenic for autosomal recessive he aring loss. ACMG/AMP criteria applied: PVS1, PM2.
Illumina Laboratory Services, Illumina	RCV000778490	SCV000914753	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2017-09-19	criteria provided, single submitter	clinical testing	The MYO15A c.6764+2T>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in two studies and identified in two individuals with congenital hearing loss. One individual had the variant in a compound heterozygous state with a second splice variant (Sloan-Heggen et al. 2016). The other individual had the c.6764+2T>A variant along with two missense variants where phase was not determined (Neveling et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000083 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited clinical evidence and due to the potential impact of splice donor variants, the c.6764+2T>A variant is classified as a variant of unknown significance, but suspicious for pathogenicity for autosomal recessive hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000778490	SCV001244801	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 4-likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 3 (MIM#600316). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 12 heterozygotes, 0 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are inconclusive. (I) 0705 - No comparable canonical splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in individuals with hearing loss and confirmed to be compound heterozygous in two of these individuals (ClinVar; PMIDs: 24123792, 26969326). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000369680	SCV001791390	pathogenic	not provided	2024-10-23	criteria provided, single submitter	clinical testing	Identified in patients with hearing loss in published literature (PMID: 26969326, 24123792); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24123792, 27375115, 31827275, 32658404, 26969326)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000369680	SCV002243602	pathogenic	not provided	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 32 of the MYO15A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs763975867, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with deafness (PMID: 24123792, 31827275). ClinVar contains an entry for this variant (Variation ID: 289237). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000369680	SCV004704079	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MYO15A: PVS1, PM2, PM3
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000369680	SCV005199425	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000369680	SCV001963673	pathogenic	not provided		no assertion criteria provided	clinical testing