Submissions for variant NM_016239.4(MYO15A):c.9620G>A (p.Arg3207His)

gnomAD frequency: 0.00026  dbSNP: rs199621031

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217646	SCV000272120	likely pathogenic	Rare genetic deafness	2020-01-03	criteria provided, single submitter	clinical testing	The p.Arg3207His variant in MYO15A has been reported in 7 individuals with hearing loss (two homozygous, four compound heterozygous with a second likely pathogenic variant, and one compound heterozygous with another variant of uncertain significance) (Bademci 2016, Sommen 2016, LMM data). This variant has been identified in 0.01% (5/35374) Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_Strong, PM2_Supporting.
Illumina Laboratory Services, Illumina	RCV000326631	SCV000401212	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2017-04-28	criteria provided, single submitter	clinical testing	The MYO15A c.9620G>A (p.Arg3207His) variant has been reported in two studies and is found in two individuals with hearing loss in a compound heterozygous state with a frameshift variant and a missense variant, respectively (Bademci et al. 2016; Sommen et al. 2016). Control data are unavailable for the variant, which is reported at a frequency of 0.02404 in the Puerto Ricans in Puerto Rico population of the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. The evidence for this variant is limited. The p.Arg3207His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000413658	SCV000491538	likely pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27375115, 27068579, 26226137)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000326631	SCV000885802	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2018-08-31	criteria provided, single submitter	clinical testing	The p.Arg3207His variant (rs199621031) is reported in the medical literature in two individuals with nonsyndromic hearing loss, one who harbored a truncating variant on the other MYO15A allele and another who had a second missense variant in MYO15A (Bademci 2016 and Sommen 2016). This variant is reported in ClinVar (Variation ID: 228973) and is found in the general population with an allele frequency of 0.0036% (10/277,202 alleles) in the Genome Aggregation Database. The arginine at codon 3207 is highly conserved considering 11 species (Alamut v2.11) but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on the available information, the clinical significance of this variant is uncertain at this time.
Invitae	RCV000413658	SCV002200876	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3207 of the MYO15A protein (p.Arg3207His). This variant is present in population databases (rs199621031, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 26226137, 27068579; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228973). 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.