Submissions for variant NM_016239.4(MYO15A):c.730G>A (p.Asp244Asn)

gnomAD frequency: 0.00032  dbSNP: rs199899548

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725020	SCV000333268	uncertain significance	not provided	2015-08-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000725020	SCV000491719	uncertain significance	not provided	2022-11-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in conjunction with additional variants in genes associated with hearing loss in an individual in published literature (Safka et al., 2020); This variant is associated with the following publications: (PMID: 32860223)
Invitae	RCV000725020	SCV001031994	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001126234	SCV001285398	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000725020	SCV001549813	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYO15A p.Asp244Asn variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs199899548), ClinVar (classified as a VUS by EGL Genetic Diagnostics and GeneDx) The variant was also identified in control databases in 113 of 276240 chromosomes at a frequency of 0.000409 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 33 of 10286 chromosomes (freq: 0.003208), European (non-Finnish) in 73 of 127466 chromosomes (freq: 0.000573), Latino in 5 of 35326 chromosomes (freq: 0.000142), Other in 1 of 7080 chromosomes (freq: 0.000141) and African in 1 of 23990 chromosomes (freq: 0.000042); it was not observed in the East Asian, European (Finnish) and South Asian population. 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. The p.Asp244 residue is 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. 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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001126234	SCV004171556	uncertain significance	Autosomal recessive nonsyndromic hearing loss 3	2023-11-24	no assertion criteria provided	clinical testing