Submissions for variant NM_000257.4(MYH7):c.5287G>A (p.Ala1763Thr)

gnomAD frequency: 0.00009  dbSNP: rs727504355

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000464078	SCV000204153	uncertain significance	Hypertrophic cardiomyopathy	2022-06-30	criteria provided, single submitter	clinical testing	The p.Ala1763Thr variant in MYH7 has been reported in 1 infant with HCM, who also carried a pathogenic variant in MYBC3, and 6 individuals with cardiomyopathy (5 with HCM, and 1 with DCM: Berge 2014, Bos 2014, Alfares 2015, Walsh 2017, LMM data). One of the individuals with HCM carried an additional pathogenic variant in MYH7 sufficient to explain their disease. This variant has also been identified in 14/126724 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504355). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1763Thr variant is uncertain. ACMG/AMP criteria applied: BS1_P.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000464078	SCV000223881	uncertain significance	Hypertrophic cardiomyopathy	2018-11-27	criteria provided, single submitter	research	The Ala1763Thr variant has been previously reported in 4 SUD cases (Dewar LJ et al., 2017), 3 DCM cases (Broch K, et al., 2018; LMM, Pers. Comm.; Phosphorus inc, ClinVar SCV000679791), 1 LVNC case (Blueprint, ClinVar SCV000264098), 3 myopathy cases (Phosphorus inc, ClinVar SCV000679793-5) and 7 HCM cases (Walsh et al., 2017; Cecconi M, et al., 2016; Bos JM, et al., 2014; Berge & Leren, 2014; Invitae, ClinVar SCV000546187; Phosphorus inc, ClinVar SCV000679792). It is present at an elevated frequency of 0.0000685 in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The MYH7 Ala1736Thr variant occurs in a conserved region, and in silico tools (SIFT, PolyPhen2, MutationTaster and CADD) support a damaging role for this variant. We have identified this variant in a single HCM proband who has no family history of disease (Ingles J et al., 2017; Burns C, et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is not rare in the general population and therefore probands cannot be counted as evidence. In silico tools predict it to deleterious (PP3), therefore we classify MYH7 Ala1763Thr as a variant of 'uncertain significance'.
Eurofins Ntd Llc (ga)	RCV000724585	SCV000229809	uncertain significance	not provided	2015-03-05	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000208237	SCV000264098	uncertain significance	Left ventricular noncompaction cardiomyopathy	2014-12-16	criteria provided, single submitter	clinical testing
Invitae	RCV000464078	SCV000546187	uncertain significance	Hypertrophic cardiomyopathy	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1763 of the MYH7 protein (p.Ala1763Thr). This variant is present in population databases (rs727504355, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, dilated cardiomyopathy or sudden death (PMID: 24111713, 24793961, 25611685, 26468400, 27532257, 27600940, 28790153, 28807990). ClinVar contains an entry for this variant (Variation ID: 177846). 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.
Phosphorus, Inc.	RCV000578112	SCV000679791	uncertain significance	Dilated cardiomyopathy 1S	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000172890	SCV000679792	uncertain significance	Hypertrophic cardiomyopathy 1	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000578027	SCV000679793	uncertain significance	MYH7-related skeletal myopathy	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV003320110	SCV000679794	uncertain significance	Myosin storage myopathy	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000577993	SCV000679795	uncertain significance	Myopathy, myosin storage, autosomal recessive	2017-08-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000464078	SCV000886838	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769433	SCV000900826	uncertain significance	Cardiomyopathy	2023-06-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769433	SCV001356062	uncertain significance	Cardiomyopathy	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction tool indicates that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 31513939, 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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.
Genetics and Genomics Program, Sidra Medicine	RCV000464078	SCV001434150	uncertain significance	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002345494	SCV002642054	uncertain significance	Cardiovascular phenotype	2023-03-09	criteria provided, single submitter	clinical testing	The p.A1763T variant (also known as c.5287G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5287. The alanine at codon 1763 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and sudden death; however, clinical details were limited (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Broch K et al. Open Heart, 2015 Oct;2:e000271; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Dewar LJ et al. Circ Cardiovasc Genet. 2017 Aug;10(4); Ramchand J et al. J Am Heart Assoc. 2020 01;9(2):e013346). In one HCM case, the individual also had a second alteration in another cardiac-related gene (Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483337	SCV002776322	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	2022-04-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724585	SCV003815412	uncertain significance	not provided	2019-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154483	SCV003845001	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.5287G>A (p.Ala1763Thr) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (6.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.5287G>A has been reported in the literature in individuals affected with HCM, DCM, or sudden unexpected death. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with a pathogenic variant has been reported (TTN c.48868C>T, p.Arg16290X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000724585	SCV004699097	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MYH7: PM2, PP3
All of Us Research Program, National Institutes of Health	RCV000769433	SCV004814353	uncertain significance	Cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1763 of the MYH7 protein. Computational prediction suggests that this variant may have 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 multiple individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 24793961, 25611685, 27532257, 27600940, 28790153), in one individual affected with dilated cardiomyopathy (PMID: 26468400), and in an individual affected with sudden unexplained death (PMID: 28807990). One individual affected with hypertrophic cardiomyopathy carried a pathogenic variant in a different gene in addition to this variant (PMID: 27600940). This variant has been identified in 21/282898 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.