Submissions for variant NM_016239.4(MYO15A):c.2194C>T (p.Pro732Ser)

gnomAD frequency: 0.00132  dbSNP: rs376451611

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727906	SCV000536140	likely benign	not provided	2021-05-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27068579)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000013	SCV000604413	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2019-02-23	criteria provided, single submitter	clinical testing	The p.Pro732Ser variant (rs376451611) has been previously identified in a cohort of patients with nonsyndromic hearing loss suspected to be of autosomal recessive inheritance (Sommen 2016). However, the p.Pro732Ser variant was found in a patient where a second pathogenic MYO15A variant was not identified, and the authors noted the weak amino acid conservation at the position and that a majority of pathogenicity predictors suggest this variant is benign (see below). This variant is also listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.13% (identified in 174 out of 130,274 chromosomes, including 1 homozygote), and listed in the ClinVar database as a variant of uncertain significance (Variation ID: 392812). The proline at codon 732 is weakly conserved considering 11 species (Alamut software v2.8.1), and computational analyses suggest this variant does not have a significant effect on MYO15A protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Pro732Ser variant cannot be determined with certainty.
Eurofins Ntd Llc (ga)	RCV000727906	SCV000855412	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727906	SCV001033757	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001000013	SCV001285519	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
PreventionGenetics, part of Exact Sciences	RCV003902625	SCV004725757	likely benign	MYO15A-related disorder	2022-10-14	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
CeGaT Center for Human Genetics Tuebingen	RCV000727906	SCV005074457	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MYO15A: BS2