Submissions for variant NM_000257.4(MYH7):c.1405G>A (p.Asp469Asn)

gnomAD frequency: 0.00004  dbSNP: rs397516106

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154581	SCV000204254	uncertain significance	not specified	2020-08-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp469Asn variant in MYH7 has been previously reported in at least 4 individuals with HCM, as well as 4 individuals referred for HCM testing with limited clinical information, 2 of whom harbored pathogenic variants in other cardiomyopathy genes (Homburger 2016 PMID 27247418, Walsh 2017 PMID 27532257, LMM data, ClinVar Variation ID 177921, Invitae and GeneDx pers. comm.). It has also been identified in 0.002% (3/129156) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016 PMID 27532257). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM1, PP3.
GeneDx	RCV000766422	SCV000208738	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	Reported in association with HCM in the published literature (Homburger et al., 2016; Walsh et al., 2017); Identified in individuals referred for HCM genetic testing at GeneDx; however, most probands harbored additional cardiogenetic variants, and segregation data is limited at this time; Not observed at a 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: 27247418, 27532257, 29300372)
Invitae	RCV001054042	SCV001218335	uncertain significance	Hypertrophic cardiomyopathy	2023-12-22	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 469 of the MYH7 protein (p.Asp469Asn). This variant is present in population databases (rs397516106, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 177921). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798499	SCV002042251	uncertain significance	Cardiomyopathy	2021-03-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390345	SCV002698894	uncertain significance	Cardiovascular phenotype	2023-01-11	criteria provided, single submitter	clinical testing	The p.D469N variant (also known as c.1405G>A), located in coding exon 12 of the MYH7 gene, results from a G to A substitution at nucleotide position 1405. The aspartic acid at codon 469 is replaced by asparagine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been detected in hypertrophic and/or dilated cardiomyopathy cohorts; however, details were limited and some reported cases may overlap (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Puckelwartz MJ et al. J Am Heart Assoc, 2021 Apr;10:e019944). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000154581	SCV000280301	uncertain significance	not specified	2012-03-05	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp469Asn (c.1405 G>A) in MYH7 The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.999). The aspartic acid at codon 469 is completely conserved across species, and neighboring amino acids are highly conserved. I could find one nearby variant reported in association with disease, p.Ile462Phe. The variant was reported online in 1 of 61439 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/ as of November 29th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766422	SCV001927021	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766422	SCV001969896	likely pathogenic	not provided		no assertion criteria provided	clinical testing