Submissions for variant NM_001145809.2(MYH14):c.3704C>T (p.Thr1235Met)

gnomAD frequency: 0.00005  dbSNP: rs200988515

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000318570	SCV000414425	uncertain significance	Autosomal dominant nonsyndromic hearing loss 4A	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.
GeneDx	RCV001354217	SCV001990313	uncertain significance	not provided	2019-07-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354217	SCV001548774	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH14 p.Thr1202Met variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200988515) and ClinVar (classified as uncertain significance by Illumina with associated condition of non-syndromic hearing loss). The variant was identified in control databases in 10 of 248778 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15424 chromosomes (freq: 0.000065), European (non-Finnish) in 7 of 112626 chromosomes (freq: 0.000062), East Asian in 1 of 17964 chromosomes (freq: 0.000056) and Latino in 1 of 34524 chromosomes (freq: 0.000029); the variant was not observed in the Ashkenazi Jewish, European (Finnish), Other, and South Asian populations. The p.Thr1202 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.