Submissions for variant NM_000257.4(MYH7):c.4402G>A (p.Glu1468Lys)

dbSNP: rs876657884

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000241907	SCV000318193	likely pathogenic	Cardiovascular phenotype	2022-01-07	criteria provided, single submitter	clinical testing	The p.E1468K variant (also known as c.4402G>A), located in coding exon 30 of the MYH7 gene, results from a G to A substitution at nucleotide position 4402. The glutamic acid at codon 1468 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy and has been shown to segregate with disease in several families (Bottillo I et al. Gene, 2016 Feb;577:227-35; Mattos BP et al. Arq. Bras. Cardiol., 2016 Sep;107:257-265; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.; Stanford pers. comm.). However, a number of relatives positive for this alteration were reportedly unaffected, suggesting incomplete penetrance. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000689327	SCV000816972	pathogenic	Hypertrophic cardiomyopathy	2023-11-27	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 1468 of the MYH7 protein (p.Glu1468Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26656175, 27247418, 27737317, 30297972; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 235033). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798726	SCV002042681	likely pathogenic	Cardiomyopathy	2022-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV003314581	SCV004014369	likely pathogenic	not provided	2023-01-11	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: 27054166, 27247418, 26656175, 27737317)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401157	SCV004122442	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.4402G>A (p.Glu1468Lys) results in a conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251430 control chromosomes (gnomAD). c.4402G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Mattos_2016, Bottillo_2016, Homburger_2016, Miller_2019) and has been reported to segregate with the disease phenotype within affected families, although multiple unaffected family members were also reported with the variant, suggesting a reduced penetrance (Mattos_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26656175, 30297972, 27247418, 27737317, 31199839). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223760	SCV000280350	uncertain significance	not specified	2014-03-18	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.Glu1468Lys (c.4402G>A) in the MYH7 gene. The variant is novel. This is a non-conservative amino acid change with an acidic polar glutamic acid replaced with a basic polar lysine. The glutamic acid at position 1468 is completely conserved across species. In silico analysis with PolyPhen predicts the variant to be probably damaging with a score of 0.990. Mutation Taster predicts this variant to be disease causing with a score of 56. No other disease-causing variants have been reported at this or nearby codons (+/- 5 codons). The variant was not observed in 200 presumed healthy individuals of Caucasian and African-American ancestry at GeneDx. There is no variation at codon 1468 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 6/20/13. There is also no variant at codon 1468 in 1000 genomes or dbSNP (as of 6/20/13). There is currently insufficient data available on the variant to determine if it causes cardiomyopathy, however the data that is available does suggest it may be pathogenic. Segregation analysis could help clarify the status of this variant.