Submissions for variant NM_016239.4(MYO15A):c.4198G>A (p.Val1400Met)

gnomAD frequency: 0.00006  dbSNP: rs749136456

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV002233817	SCV002512125	pathogenic	Nonsyndromic genetic hearing loss	2021-07-27	reviewed by expert panel	curation	The allele frequency of the c.4198G>A (p.Val1400Met) variant in the MYO15A gene is 0.01980% (7/35356) of African/African-American chromosomes by gnomAD. This variant has been reported to segregate with hearing loss in at least 3 separate families (PP1_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). This variant has been detected in 10 probands with nonsyndromic hearing loss. For 2 of those probands, a pathogenic or suspected-pathogenic variant was observed in trans, in 1 a rare variant of unknown significance was observed in trans, and in 7 the variant was observed in the homozygous state (PM3_Strong; PMIDs: 27870113, 20642360; Partners LMM internal data SCV000966848.2). Additionally, the REVEL computational prediction analysis tool produced a score of 0.891, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PP3.
Illumina Laboratory Services, Illumina	RCV000779207	SCV000915748	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2018-10-10	criteria provided, single submitter	clinical testing	The MYO15A c.4198G>A (p.Val1400Met) variant has been reported in two studies and is found in a total of 39 probands with hearing loss, including 27 probands with hearing loss from seven families of Turkish or Brazilian origin who carried the variant in a homozygous state and 12 probands from two Brazilian families who carried the variant in a compound heterozygous state with a second missense variant (Cengiz et al. 2010; Manzoli et al. 2016). Segregation analysis in one Turkish family showed both affected siblings to be homozygous for the p.Val1400Met variant, while an unaffected sibling and both unaffected parents were heterozygous. The p.Val1400Met variant was found in a heterozygous state in one of 20 controls and is reported at a frequency of 0.00020 in the Latino population of the Genome Aggregation Database. Based on the evidence, the p.Val1400Met variant is classified as pathogenic for the recessive form of nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825533	SCV000966848	pathogenic	Rare genetic deafness	2023-06-20	criteria provided, single submitter	clinical testing	The p.Val1400Met variant in MYO15A has been reported in 12 probands with sensorineural hearing loss, including 7 homozygous individuals, 3 individuals who were compound heterozygous for a variant of uncertain significance, 1 individual with a second likely pathogenic variant and 1 individual who was confirmed to have a nonsense variant present in trans (Cengiz 2010 PMID: 20642360, Manzoli 2016 PMID: 27870113, Fu 2022 PMID: 35346193, LMM unpublished data). Furthermore, the variant segregated with hearing loss in 12 affected members of 7 families, including 2 compound heterozygous individuals (Cengiz 2010 PMID: 20642360, Manzoli 2016 PMID: 27870113, LMM unpublished data). This variant has also been identified in 0.02% (1/4818) of South Asian and 0.0066% (1/15266) Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2); however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant was classified as Pathogenic on July 27, 2021 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 632271). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity on its own. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PP1_Strong, PM3_Strong, PP3, PM2_Supporting.
GeneDx	RCV001561220	SCV001783775	pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35346193, 26242193, 27375115, 34652575, 20642360, 27870113, 33398081)
Molecular Diagnosis Center for Deafness	RCV000779207	SCV001984898	pathogenic	Autosomal recessive nonsyndromic hearing loss 3		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000779207	SCV002017857	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2019-12-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000779207	SCV002810282	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2022-02-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001561220	SCV004298140	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1400 of the MYO15A protein (p.Val1400Met). This variant is present in population databases (rs749136456, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 20642360, 27870113, 33398081, 35346193). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 632271). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. For these reasons, this variant has been classified as Pathogenic.