Submissions for variant NM_000257.4(MYH7):c.3382G>A (p.Ala1128Thr)

gnomAD frequency: 0.00011  dbSNP: rs199552354

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758075	SCV000564444	likely benign	Cardiomyopathy	2021-03-22	reviewed by expert panel	curation	The c.3382G>A (p.Ala1128Thr) variant in MYH7 has been identified in 0.02% (FAF 95% CI; 10/34232) of Latino chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172567	SCV000051005	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035852	SCV000059503	likely benign	not specified	2017-08-06	criteria provided, single submitter	clinical testing	The p.Ala1128Thr variant in MYH7 has been reported in 1 individual with DCM (Rod riguez-Garcia 2011 - abstract only). It has also been identified by our laborat ory in 2 children with DCM and 1 adult with HCM - one of the children with DCM i nherited the variant from an unaffected parent (LMM unpublished data). This vari ant has been identified in 26/236012 chromosomes in the gnomAD database (http:// gnomad.broadinstitute.org, dbSNP rs199552354). Computational prediction tools an d conservation analyses do not provide strong support for or against an impact t o the protein. In summary, given the inconsistent phenotypic observations (both DCM and HCM), 26 occurrences in the general population, and lack of disease in a carrier parent of an affected child, the clinical significance of the p.Ala1128 Thr variant is likely benign.
GeneDx	RCV000035852	SCV000208540	uncertain significance	not specified	2017-02-06	criteria provided, single submitter	clinical testing	p.Ala1128Thr (GCC>ACC): c.3382 G>A in exon 27 of the MYH7 gene (NM_000257.2). The A1128T variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. A1128T results in a non-conservative amino acid substitution of a non-polar Alanine with a neutral, polar Threonine at a position that is conserved in mammals. While in silico analysis predicts A1128T is benign to the protein structure/function, mutations in nearby codons (E1116K, L1135R) have been reported in association with HCM, suggesting that there is functional importance of this region of the protein. The A1128T variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM,DCM-CRDM panel(s).
Invitae	RCV000471337	SCV000546254	uncertain significance	Hypertrophic cardiomyopathy	2024-01-29	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 1128 of the MYH7 protein (p.Ala1128Thr). This variant is present in population databases (rs199552354, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 31513939). ClinVar contains an entry for this variant (Variation ID: 42959). 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.
Center for Human Genetics, University of Leuven	RCV000471337	SCV000886835	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000758075	SCV000902575	uncertain significance	Cardiomyopathy	2023-03-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1128 of the MYH7 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a dilated cardiomyopathy subject (Rodriguez-Garcia et al., 2011, abstract) as well as in multiple healthy individuals free of cardiovascular disorders (PMID: 23861362, 24510615). This variant has been identified in 26/236012 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000758075	SCV001333905	likely benign	Cardiomyopathy	2022-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035852	SCV002547934	uncertain significance	not specified	2023-09-15	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.3382G>A (p.Ala1128Thr) results in a non-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 allele was found at a frequency of 0.00011 in 240554 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (0.00011 vs 0.0013), allowing no conclusion about variant significance. c.3382G>A has been reported in the literature in individuals affected with Cardiomyopathy (Homburger_2016, Ho_2018, Kelly_2018, Luo_2020, Robyns_2020), but it has also been reported in unaffected individuals (Ng_2013, Kapplinger_2014). Furthermore, one ClinVar submitter reports internal data of the variant identified in 2 children with DCM and 1 adult with HCM, with one of the children with DCM having inherited the variant from an unaffected parent (SCV000059503.5). A co-occurrence with a pathogenic variant has been reported (TTN c.3382G>A, p.Gln12086X; Internal testing), providing supporting evidence for a benign role. 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: 23861362, 24510615, 27247418, 27930701, 29300372, 30297972, 31513939, 31941943). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four ClinVar submitters including an expert panel (ClinGen Cardiomyopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as likely benign and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002453299	SCV002616127	likely benign	Cardiovascular phenotype	2023-04-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172567	SCV004563775	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	The MYH7 c.3382G>A; p.Ala1128Thr variant (rs199552354) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (Ho 2018, Luo 2020, Robyns 2020), but is also found in healthy controls (Kapplinger 2014, Ng 2013). This variant is also reported in ClinVar (Variation ID: 42959), and is found in the Latino/Admixed American population with an allele frequency of 0.029% (10/34232 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.404). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ho CY et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation. 2018 Oct 2;138(14):1387-1398. PMID: 30297972. Kapplinger JD et al. Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. J Cardiovasc Transl Res. 2014 Apr;7(3):347-61. PMID: 24510615. Luo Q et al. Retrospective analysis of clinical phenotype and prognosis of hypertrophic cardiomyopathy complicated with hypertension. Sci Rep. 2020 Jan 15;10(1):349. PMID: 31941943. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. PMID: 23861362. Robyns T et al. Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. Eur J Med Genet. 2020 Mar;63(3):103754. PMID: 31513939.
All of Us Research Program, National Institutes of Health	RCV000758075	SCV004814399	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1128 of the MYH7 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a dilated cardiomyopathy subject (Rodriguez-Garcia et al., 2011, abstract) as well as in multiple healthy individuals free of cardiovascular disorders (PMID: 23861362, 24510615). This variant has been identified in 26/236012 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.