Submissions for variant NM_000257.4(MYH7):c.4159G>A (p.Glu1387Lys)

dbSNP: rs730880792

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766457	SCV000208573	uncertain significance	not provided	2023-10-17	criteria provided, single submitter	clinical testing	Identified in a family with HCM who also harbored c.(A934V) in cis (Wang et al., 2019); 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: 28687478, 27247418, 21310275, 29121657, 34542152, 31638223)
Invitae	RCV000457747	SCV000546215	uncertain significance	Hypertrophic cardiomyopathy	2023-06-24	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 181244). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 27247418, 29121657, 31638223). This variant is present in population databases (rs730880792, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1387 of the MYH7 protein (p.Glu1387Lys).
Ambry Genetics	RCV000621684	SCV000736922	uncertain significance	Cardiovascular phenotype	2021-02-04	criteria provided, single submitter	clinical testing	The p.E1387K variant (also known as c.4159G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4159. The glutamic acid at codon 1387 is replaced by lysine, an amino acid with similar properties. This aleratation has been detected in hypertrophic cardiomyopathy (HCM) cohorts; however, details were limited (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Viswanathan SK et al. PLoS One. 2017 Nov;12(11):e0187948). This variant co-occurred with a second MYH7 variant in a family with HCM (Wang B et al. Mol Med Rep. 2019 Dec;20(6):5229-5238). Another alteration affecting the same amino acid (p.E1387Q, c.4159G>C) has also been reported in association with HCM (O'Mahony C et al. Circ Arrhythm Electrophysiol, 2016 Jun;9). 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.
Illumina Laboratory Services, Illumina	RCV001109893	SCV001267274	uncertain significance	Dilated cardiomyopathy 1S	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV003320120	SCV001267275	uncertain significance	Myosin storage myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001109895	SCV001267276	uncertain significance	MYH7-related skeletal myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001109896	SCV001267277	uncertain significance	Hypertrophic cardiomyopathy 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001109896	SCV001433094	uncertain significance	Hypertrophic cardiomyopathy 1	2019-05-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486714	SCV004239467	uncertain significance	Cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158638	SCV000280347	uncertain significance	not specified	2014-07-07	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.Glu1387Lys (c.4159 G>A) in the MYH7 gene. The variant has been seen in at least one unrelated cases of HCM (not including this patient's family). No segregation data is available. GeneDx notes the variant is novel, however I found a report of the variant in a poster from the 2010 European Society of Cardiology meeting (Waldmuller et al 2010, Http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=P2062). I could not find a report of this variant in any publications by the same group. In the poster they report observing the variant in one of 20 patents with "suspected familial HCM" who underwent sequencing of 17 cardiomyopathy associated genes. Ancestry is not noted, however the report is by a German group. No segregation data was reported. The same group also reported on the variant, very likely from the same case, at the 2010 Congress of the German Human Genetics Society (Waldmuller et al 2010). It is not in ClinVar. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 0.999). The glutamic acid at codon 1387 is completely conserved across species, as are neighboring amino acids. I could not find any other variants reported in association with disease at this codon, however there are variants reported in association with cardiomyopathy at nearby codons (p.Ala1379Thr (per the Seidman's database), p.Arg1382Gln, p.Arg1382Trp (per GeneDx report, referencing HGMD)). In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 1387 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 23rd 2014).There is also no variation at this codon listed in dbSNP (as of July 24th, 2014).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766457	SCV001932482	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766457	SCV001952642	likely pathogenic	not provided		no assertion criteria provided	clinical testing