Submissions for variant NM_001145809.2(MYH14):c.5876G>A (p.Arg1959Gln)

gnomAD frequency: 0.00012  dbSNP: rs200878464

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037053	SCV000060709	uncertain significance	not specified	2013-04-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg1959Gln vari ant in MYH14 has not been reported in the literature nor previously identified b y our laboratory in any other families. This variant has been identified in 0.02 % (2/8402) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Although this vari ant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical amino acid prop erties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg1959Gl n variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. It is noted that this individual shares this vari ant with his daughter but does not have a hearing loss suggesting a more benign role for this variant assuming complete penetrance of MYH14 pathogenic variants. In summary, the clinical significance of this variant cannot be determined with certainty; however, based upon its presence in an unaffected family member, we would lean towards a more benign role.
CeGaT Center for Human Genetics Tuebingen	RCV000416232	SCV000493229	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	MYH14: BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416232	SCV002111937	uncertain significance	not provided	2021-02-12	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 44077). This variant is present in population databases (rs200878464, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This sequence change replaces arginine with glutamine at codon 1918 of the MYH14 protein (p.Arg1918Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Ambry Genetics	RCV004018827	SCV005014785	uncertain significance	Inborn genetic diseases	2024-12-06	criteria provided, single submitter	clinical testing	The c.5753G>A (p.R1918Q) alteration is located in exon 40 (coding exon 39) of the MYH14 gene. This alteration results from a G to A substitution at nucleotide position 5753, causing the arginine (R) at amino acid position 1918 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.