Submissions for variant NM_000257.4(MYH7):c.925G>A (p.Asp309Asn)

gnomAD frequency: 0.00002  dbSNP: rs730880923

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158882	SCV000208817	likely pathogenic	not provided	2024-04-05	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: 23233322, 8490051, 27247418, 27532257, 28606303, 28640247, 1472461, 35653365, 34542152, 29300372)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536809	SCV000623759	pathogenic	Hypertrophic cardiomyopathy	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 309 of the MYH7 protein (p.Asp309Asn). This variant is present in population databases (rs730880923, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23233322, 27247418, 27532257, 28640247; internal data). ClinVar contains an entry for this variant (Variation ID: 181402). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584771	SCV000692501	uncertain significance	Hypertrophic cardiomyopathy 1	2017-03-10	criteria provided, single submitter	research	The MYH7 Asp309Asn variant has been previously reported in 2 HCM probands (Kassem HSh, et al., 2013; Walsh R, et al., 2017). The variant is present at low frequency in the Exome Aggregation Consortium dataset (MAF=0.000025; http://exac.broadinstitute.org/). The variant was identified in a HCM patient (from the UK), that was diagnosed post- resuscitated cardiac arrest. There is no family history of disease or sudden cardiac death. The proband also harbours a second variant (TNNT2 Asn269Ser). Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, based on rarity in the general population and limited evidence in the literature, we classify MYH7 Asp309Asn as a variant of "uncertain significance".
Color Diagnostics, LLC DBA Color Health	RCV001187174	SCV001353889	uncertain significance	Cardiomyopathy	2022-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 309 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23233322, 27247418, 27532257, 28640247). This variant has been identified in 4/251396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional clinical data are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001270160	SCV001367501	uncertain significance	Congenital myopathy with fiber type disproportion	2020-02-08	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001187174	SCV003838767	likely pathogenic	Cardiomyopathy	2021-10-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158882	SCV004236711	uncertain significance	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000584771	SCV005399436	likely pathogenic	Hypertrophic cardiomyopathy 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (4 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is found within the head region, which is enriched with pathogenic missense variants (PMID: 29300372). (SP) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as both a VUS and likely pathogenic. However, the variant has been reported in at least six individuals with HCM. (ClinVar, PMID: 23233322, PMID: 28640247, PMID: 27532257). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign