Submissions for variant NM_000257.4(MYH7):c.5395G>A (p.Glu1799Lys)

dbSNP: rs730880816

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV001797641	SCV002041485	uncertain significance	Primary dilated cardiomyopathy	2021-12-09	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.5395G>A (p.Glu1799Lys) variant has been identified in at least 5 individuals with DCM, including 1 infant with DCM and LVNC (PS4_Supporting; Mazzarotto 2020 PMID: 3198322; Petrovsky National Research Centre of Surgery - The Federal Agency for Scientific Organizations ClinVar Submission Accession: SCV001445827.; CHEO pers. comm.; GeneDx pers. comm.; OMGL pers. comm.). This variant has also been reported in 2 individuals with LVNC (Takasaki 2018 PMID:30188508; Ambry pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3.
GeneDx	RCV000158698	SCV000208633	likely pathogenic	not provided	2012-12-04	criteria provided, single submitter	clinical testing	p.Glu1799Lys (GAA>AAA):c.5395 G>A in exon 37 of the MYH7 gene (NM_000257.2). The Glu1799Lys variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu1799Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic Acid residue with a positively charged Lysine residue at a position that is conserved across species. In silico analysis predicts Glu1799Lys is probably damaging to the protein structure/function. Mutations in nearby residues (D1792G, Q1794E, E1801G, G1808A) have been reported in association with DCM, further supporting the functional importance of this region of the protein. Furthermore, the Glu1799Lys variant was not reported in the 1000 Genomes database (Kersey P et al., 2010), and the NHLBI ESP Exome Variant Server reports Glu1799Lys was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, Glu1799Lys is a good candidate for a disease-causing mutation. The variant is found in DCM panel(s).
Blueprint Genetics	RCV000158698	SCV000927133	likely pathogenic	not provided	2017-01-25	criteria provided, single submitter	clinical testing
Invitae	RCV000818295	SCV000958898	uncertain significance	Hypertrophic cardiomyopathy	2024-01-04	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 1799 of the MYH7 protein (p.Glu1799Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 30188508, 31983221, 35288587). ClinVar contains an entry for this variant (Variation ID: 181278). 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%. 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	RCV001170483	SCV001333064	uncertain significance	Cardiomyopathy	2021-07-16	criteria provided, single submitter	clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001267834	SCV001445827	uncertain significance	See cases	2020-11-18	criteria provided, single submitter	clinical testing	We observed a genetic variant c.5395G>A (p.E1799K) in MYH7 gene in a 6-months old male proband. He was diagnosed with dilatation cardimyopathy and left ventricular non-compaction. The p.E1799K genetic variant is not present in gnomAD database, and the bioinformatic evidence is controversial. The online in silico resources predict the p.E1799K genetic variant to be probably pathogenic. Additionally, the p.E1799K genetic variant is a missense variant in MYH7 gene, with z-score of 3.93, therefore, MYH7 gene is probably less tolerant to missense variants. However, no functional studies are available for the p.E1799K genetic variant and the results of family screening were inconclusive. We classify the p.E1799K genetic variant to be the variant of uncertain clinical significance.
Ambry Genetics	RCV002345538	SCV002646715	uncertain significance	Cardiovascular phenotype	2018-06-20	criteria provided, single submitter	clinical testing	The p.E1799K variant (also known as c.5395G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5395. The glutamic acid at codon 1799 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155094	SCV003845157	uncertain significance	not specified	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.5395G>A (p.Glu1799Lys) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) 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 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5395G>A has been reported in the literature in individuals affected with Cardiomyopathy without evidence of cosegregation (Takasaki_2018, Mazzarotto_2020, Lesurf_2022). These reports do not provide unequivocal conclusions about association of the variant with Left Ventricular Noncompaction or Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, classifying it as uncertain significance (n=5, including expert panel) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.