Submissions for variant NM_000257.4(MYH7):c.2707G>A (p.Glu903Lys)

dbSNP: rs730880756

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003332128	SCV000208499	likely pathogenic	not provided	2023-09-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15358028, 31513939, 34667425, 27532257, 29300372, 20031618)
Center for Human Genetics, University of Leuven	RCV000768487	SCV000886791	likely pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000768487	SCV000948076	uncertain significance	Hypertrophic cardiomyopathy	2022-05-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 903 of the MYH7 protein (p.Glu903Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20031618, 31513939). ClinVar contains an entry for this variant (Variation ID: 181202). 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. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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.
3billion	RCV003313941	SCV004013808	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29300372. Predicted Consequence/Location:). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYH7 related disorder (PMID: 15358028). Different missense changes at the same codon (p.Glu903Gln, p.Glu903Gly) have been reported to be associated with MYH7 related disorder (PMID: 18403758, 25524337). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Regional Center For Medical Genetics Timis, Louis Turcanu Emergency Hospital for Children Timisoara	RCV003313941	SCV005061761	likely pathogenic	Hypertrophic cardiomyopathy 1	2024-05-24	criteria provided, single submitter	research	The variant is not present in healthy population databases (gnomAD v4.1.0, genomes and exomes). In silico predictions supports the pathogenicity of the variant (REVEL score = 0.88 > 0.75). Other P/LP variants are reported in the literature in Hypertrophic cardiomyopathy for the same amino acid residue. The variant was previously described in patients with hypertrophic cardiomyopathy (PMID: 15358028). Therefore the variant was classified as likely pathogenic, according to ACMG 2015 guidelines.