Submissions for variant NM_016239.4(MYO15A):c.7124_7127del (p.Asp2375fs)

dbSNP: rs780170125

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000504331	SCV000595891	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2016-08-25	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000605806	SCV000713100	pathogenic	Rare genetic deafness	2017-08-17	criteria provided, single submitter	clinical testing	The p.Asp2375fs variant in MYO15A has been previously reported in two individual s with hearing loss who also had a second variant on the remaining copy of MYO15 A (Vona 2014, Sloan-Heggen 2015). This variant has also been identified in 11/1 26686 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs763553435). Although this variant has been see n in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, w hich alters the protein?s amino acid sequence beginning at position 2375 and lea ds to a premature termination codon 41 amino acids downstream. This alteration i s then predicted to lead to a truncated or absent protein. Loss of function of the MYO15A gene is an established disease mechanism in autosomal recessive nonsy ndromic sensorineural hearing loss. In summary, this variant meets criteria to b e classified as pathogenic for autosomal recessive hearing loss based on the pre dicted impact on the protein, compound heterozygosity in multiple affected indiv iduals, and low allele frequency in the general population consistent with a rec essive carrier frequency.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626936	SCV000747639	pathogenic	Congenital sensorineural hearing impairment	2017-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001653861	SCV001871034	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in 0.0043% (12/280936 alleles) in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24875298, 26969326, 32860223)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001653861	SCV002246049	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp2375Valfs*41) in the MYO15A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs780170125, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 24875298, 26969326, 32860223). ClinVar contains an entry for this variant (Variation ID: 435919). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000504331	SCV002769301	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2020-05-04	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 35 of 66). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. More than 10 NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 3 unrelated patients with hearing loss (ClinVar, PMID: 24875298). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GenomeConnect, ClinGen	RCV000504331	SCV002075196	not provided	Autosomal recessive nonsyndromic hearing loss 3		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 06-28-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
PreventionGenetics, part of Exact Sciences	RCV004745429	SCV005347679	pathogenic	MYO15A-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The MYO15A c.7124_7127delACAG variant is predicted to result in a frameshift and premature protein termination (p.Asp2375Valfs*41). This variant has been reported as causative for autosomal recessive nonsyndromic hearing loss (Table S3, Sloan-Heggen et al. 2016. PubMed ID: 26969326; Table S1, Safka Brozkova et al. 2020. PubMed ID: 32860223; Vona et al. 2014. PubMed ID: 24875298). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MYO15A are expected to be pathogenic. This variant is interpreted as pathogenic.