Submissions for variant NM_000257.4(MYH7):c.4954G>T (p.Asp1652Tyr)

gnomAD frequency: 0.00004  dbSNP: rs397516233

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035941	SCV000059592	uncertain significance	not specified	2014-04-04	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766465	SCV000208613	uncertain significance	not provided	2023-09-15	criteria provided, single submitter	clinical testing	Reported in association with different cardiomyopathy presentations (DCM, HCM and restrictive cardiomyopathy) (PMID: 19659763, 21302287, 27247418, 27532257, 28356264, 28408708, 32894683 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33588347, 27532257, 26633542, 27247418, 21302287, 28790153, 28356264, 33495597, 19659763, 28408708, 32894683, 36129056, 34542152, 32528171, 36243179)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584779	SCV000692493	uncertain significance	Hypertrophic cardiomyopathy 1	2017-03-09	criteria provided, single submitter	research	This MYH7 Asp1652Tyr variant has been described in two Italian HCM patients (Frisso G, et al., 2009; Roncarati R, et al., 2011). Segregation analysis provided by Frisso G et al. (2009) identified two family members who also carry this variant. Both members however, did not have typical HCM characteristics but rather a dilated (proband's sister) and restrictive (proband's father) cardiomyopathy phenotype. We have identified this MYH7 Asp1652Tyr variant in an isolated HCM patient of North West European descent. Clinical screening of the family revealed no family history of HCM and/or sudden cardiac death. We note that additional uncertain variants have been identified in the proband which may contribute to the disease phenotype (MYL2 Ala13Thr; DSG2 Asp535Glu). The MYH7 Asp1652Tyr variant is absent in 1000 genomes project (http://www.1000genomes.org/), and has a frequency of 0.00002475 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Aspartic acid at position 1652 is highly conserved across distantly related species, and computational tools predict the Asp1652Tyr to be "deleterious" (SIFT) and "disease-causing" (MutationTaster). Additionally, Polyphen_HCM (Jordan DM, et al., 2011) predicts that this MYH7 Asp1652Tyr variant is causative of the disease. Based on this information, we classify MYH7 Asp1652Tyr as a variant of "uncertain significance".
Invitae	RCV000694818	SCV000823280	uncertain significance	Hypertrophic cardiomyopathy	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1652 of the MYH7 protein (p.Asp1652Tyr). This variant is present in population databases (rs397516233, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy or limb-girdle weakness (PMID: 19659763, 21302287, 27247418, 27532257, 28356264, 28790153, 32528171). ClinVar contains an entry for this variant (Variation ID: 43047). 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	RCV000769441	SCV000900834	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769441	SCV001350839	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 1652 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 individuals affected with hypertrophic cardiomyopathy (PMID: 19659763, 21302287, 27247418, 27532257, 28356264, 28790153, 33588347, 33495596, 33495597). This variant has also been identified in 12/251342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000766465	SCV002501617	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	RCV000584779	SCV002765157	uncertain significance	Hypertrophic cardiomyopathy 1	2021-09-23	criteria provided, single submitter	clinical testing	The c.4954G>T (p.Asp1652Tyr) MYH7 variant has been reported in our laboratory in a 44-year-old patient with diagnosis of hypertrophic cardiomyopathy. Mother (with permanent atrial fibrillation and pacemaker) and maternal grandmother with the same diagnosis. This variant is present in population databases (gnomAD allele frequency 0.00004774, 12/251342 alleles) being more frequent in the Latino population (gnomAD allele frequency 0.0001446). This variant has been previously reported in a patients with hypertrophic cardiomyopathy [PMID 28790153, 27247418, 27532257, 28356264]. ClinVar contains an entry for this variant (Variation ID: 43047). In silico analysis (CADD, Mutation Taster, SIFT, Provean, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. Some in silico splicing studies predict that it affects the natural splicing acceptor of intron 34, but there are no in vitro or in vivo functional studies, as well as RNA studies that have verified this aspect. In summary, c.4954G>T (p.Asp1652Tyr) MYH7 variant is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002490490	SCV002784028	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-08-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000766465	SCV003817676	uncertain significance	not provided	2021-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298058	SCV003993384	uncertain significance	Cardiovascular phenotype	2023-06-04	criteria provided, single submitter	clinical testing	The p.D1652Y variant (also known as c.4954G>T) is located in coding exon 33 of the MYH7 gene. The aspartic acid at codon 1652 is replaced by tyrosine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 33. This variant has been detected in cohorts with hypertrophic cardiomyopathy and neuromuscular phenotypes (Frisso G et al. Clin Genet, 2009 Jul;76:91-101; Roncarati R et al. J Cell Physiol, 2011 Nov;226:2894-900; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Töpf A et al. Genet Med, 2020 Sep;22:1478-1488). This variant has also been detected in individuals from a cohort not selected for the presence of cardiovascular or neuromuscular phenotypes; however, details were limited (Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). 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.