Submissions for variant NM_001145809.2(MYH14):c.1229G>A (p.Arg410His)

gnomAD frequency: 0.00013  dbSNP: rs374720181

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001129448	SCV001288974	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	RCV001558118	SCV001779999	uncertain significance	not provided	2020-09-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV001558118	SCV004140506	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MYH14: BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001558118	SCV004516649	uncertain significance	not provided	2023-02-11	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 402 of the MYH14 protein (p.Arg402His). This variant is present in population databases (rs374720181, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 892797). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function.