Submissions for variant NM_016239.4(MYO15A):c.3203G>T (p.Cys1068Phe)

gnomAD frequency: 0.00047  dbSNP: rs189061214

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825786	SCV000967253	likely benign	not specified	2019-02-14	criteria provided, single submitter	clinical testing	The p.Cys1068Phe variant in MYO15A is classified as likely benign because it has been identified in 0.07% (86/128286) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and because computational prediction tools and conservation analysis suggest that this variant may not impact the protein. ACMG/AMP criteria applied: BS1_Supporting, BP4.
Illumina Laboratory Services, Illumina	RCV001123766	SCV001282631	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001123766	SCV001477518	likely benign	Autosomal recessive nonsyndromic hearing loss 3	2019-12-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001354263	SCV001710749	likely benign	not provided	2024-09-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001354263	SCV002031035	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36672845)
Ambry Genetics	RCV002538228	SCV003679101	uncertain significance	Inborn genetic diseases	2022-05-30	criteria provided, single submitter	clinical testing	The c.3203G>T (p.C1068F) alteration is located in exon 2 (coding exon 1) of the MYO15A gene. This alteration results from a G to T substitution at nucleotide position 3203, causing the cysteine (C) at amino acid position 1068 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354263	SCV001548834	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYO15A p.Cys1068Phe variant was not identified in the literature but was identified in dbSNP (ID: rs189061214) and ClinVar (classified as likely benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 126 of 280466 chromosomes at a frequency of 0.0004493 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 9 of 7136 chromosomes (freq: 0.001261), Latino in 25 of 35370 chromosomes (freq: 0.000707), European (non-Finnish) in 86 of 128286 chromosomes (freq: 0.00067), African in 4 of 24168 chromosomes (freq: 0.000166), Ashkenazi Jewish in 1 of 10342 chromosomes (freq: 0.000097) and South Asian in 1 of 30602 chromosomes (freq: 0.000033), but was not observed in the East Asian or European (Finnish) populations. The p.Cys1068 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.