ClinVar Genomic variation as it relates to human health

The NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr) variant has been identified in at least 14 individuals with HCM, 2 of whom had an additional variant in another gene that may contribute to their disease, 1 individual with RCM with another pathogenic MYH7 variant, and 5 individuals with DCM including 2 that also had disease-causing variants (Richard 2003 PMID:12707239; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Walsh 2017 PMID: 27532257; Ho 2018 PMID:30297972; Ambry pers. comm.; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm). This variant has also been identified in 1 individual with LVNC requiring transplant who also had 2 pathogenic MYBPC3 variants, 1 individual with Brugada syndrome, and 2 individuals with myopathy - 1 with myofibrillar myopathy and 1 with distal and axial myopathy (Hertz 2014 PMID:25467552; Evilä 2016 PMID:26627873; Chanson 2016 PMID:26969127; Liu 2020 PMID:31918855). This variant has been observed to segregate with DCM in 1 relative of a proband with DCM as well as not segregate with HCM in an affected sibling of a proband with HCM (OMGL per. comm.). Because of the variability in phenotypes observed in individuals with this variant and because PS4 is only applicable when the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Additionally, the segregation data is currently insufficient to establish segregation or non-segregation with disease and therefore neither PP1 nor BS4 were applied. This variant has been identified in 0.008% (FAF 95% CI; 17/129,190) of European chromosomes in gnomAD v.2.1.1 (http://gnomad.broadinstitute.org) and is above the threshold of 0.004%, therefore PM2 cannot be applied. Computational prediction tools and conservation do not provide evidence for or against an impact to the protein. In summary, due to conflicting evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): None.

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1777 of the MYH7 protein (p.Ala1777Thr). This variant is present in population databases (rs200939753, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 24793961, 27247418, 27532257, 32894683, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 177697). 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.

The p.Ala1777Thr variant in MYH7 has been reported in 6 individuals with HCM, 1 individual with DCM, 1 individual with myopathy, and 1 individual with RCM who carried a second pathogenic MYH7 variant (Richard 2003, Ng 2013, Walsh 2017, Evila 2016, Bos 2014, Hertz 2014, LMM data). The p.Ala1777Thr variant has also been identified in 17/126714 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200939753). Clinvar: Path (University Hosp of Strasbourg), LP (Blueprint, ClinSeq), VUS (GeneDx, Invitae, Ambry, MYH7 expert panel). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Furthermore, in vitro functional studies suggest that the variant may not impact protein function (Wallefeld 2010); however, these types of assays may not accurately represent biological function. In summary, given the broad phenotypic spectrum associated with this variant and the presence of conflicting data, the clinical significance of the p.Ala1777Thr variant is uncertain.

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 25467552, 23447461, 25961035, 26969127, 26627873, 27532257, 31918855, 36095024, 23861362, 33673806, 29300372, 24793961, 32894683, 34542152, 12707239)

This missense variant replaces alanine with threonine at codon 1777 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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: 12707239, 24793961, 27532257, 30297972), suspected hypertrophic cardiomyopathy (PMID: 33673806), dilated cardiomyopathy (PMID: 27532257), and Brugada syndrome (PMID: 25467552). Additionally, this variant has been reported in an individual affected with left ventricular noncompaction cardiomyopathy who also carried two pathogenic variants in the MYBPC3 gene (PMID: 31918855). This variant has been reported in individuals from a cohort of patients undergoing whole exome sequencing that were not selected for cardiomyopathy, arrhythmia or a family history of sudden death (PMID: 23861362, 34542152). This variant has also been identified in 21/282890 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.

This missense variant replaces alanine with threonine at codon 1777 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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: 12707239, 24793961, 27532257, 30297972), suspected hypertrophic cardiomyopathy (PMID: 33673806), dilated cardiomyopathy (PMID: 27532257), and Brugada syndrome (PMID: 25467552). Additionally, this variant has been reported in an individual affected with left ventricular noncompaction cardiomyopathy who also carried two pathogenic variants in the MYBPC3 gene (PMID: 31918855). This variant has been reported in individuals from a cohort of patients undergoing whole exome sequencing that were not selected for cardiomyopathy, arrhythmia or a family history of sudden death (PMID: 23861362, 34542152). This variant has also been identified in 21/282890 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.

Variant summary: MYH7 c.5329G>A (p.Ala1777Thr) 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 6.8e-05 in 251488 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. 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.5329G>A has been reported in the literature in individuals affected with Cardiomyopathy. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. 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: 12707239, 23861362, 24793961, 27247418, 27532257, 25467552, 29300372, 33673806). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=10) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.A1777T variant (also known as c.5329G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5329. The alanine at codon 1777 is replaced by threonine, an amino acid with similar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation. 2003;107(17):2227-32); Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ambry internal data). This alteration was also identified in a patient reported to have distal and axial myopathy, a patient reported to have myofibrillar myopathy (Evil&auml; A et al. Neuromuscul Disord. 2016;26(1):7-15; Chanson JB et al. Eur J Neurol. 2016; 23(6):1086-92). This variant has been detacted in a case with Brugada syndrome and co-occurred with MYBPC3 variants in an individual with noncompaction cardiomyopathy (Hertz CL et al. Int. J. Legal Med., 2015 Jul;129:793-800; Liu S et al. Int J Cardiol. 2020 03;302:117-123). This variant has also been detected in individuals from a cohort not indicated as having cardiomyopathy or skeletal myopathy; however details were limited (Park J et al. Hum Mol Genet. 2022 03;31(5):827-837). This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). 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.