Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000694881 | SCV001842662 | uncertain significance | Hypertrophic cardiomyopathy | 2021-06-16 | reviewed by expert panel | curation | The c.1046T>C (p.Met349Thr) variant in MYH7 has been reported in at least 6 individuals with HCM (PS4_Supporting; Jeschke 1998 PMID:9544842; GeneDx: pers comm., Ambry: pers comm, Invitae: pers comm), 1 of whom also had additional variants in other HCM-associated genes (Ambry pers comm;). Additionally, one of these individuals also had severe, early-onset (<20 yo) presentation of HCM and carried a second de novo MYH7 variant on the second allele that was classified as pathogenic by this expert panel (p.Arg719Trp, ClinVar variation ID:14104). This variant has also been reported in 1 individual with unspecified heart disease, 1 with LVH, and 1 with arrhythmia, and 1 with LVNC with atrial and ventricular septal defect (Ambry pers comm.; GeneDX pers comm.; Invitae pers comm.; OMGL pers comm.). This variant has also been identified in 0.007% (1/15378) of European chromosomes, in gnomAD (v2.1.1; http://gnomad.broadinstitute.org). This represents only a fraction of the total European chromosomes, suggesting low coverage at this locus. Therefore, data from large population studies are insufficient to assess the frequency of this variant and apply PM2. Additionally, since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM1. |
| Gene |
RCV000127019 | SCV000170552 | uncertain significance | not provided | 2021-10-01 | criteria provided, single submitter | clinical testing | Reported previously in one individual with HCM who also harbored another de novo MYH7 variant on the opposite allele; he M349T variant was maternally inherited and was identified in several other relatives, all of whom were asymptomatic (Jeschke et al., 1998); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#14094; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 9544842, 10900182, 15737656, 18761664, 26272908, 21310275, 11968089) |
| Ambry Genetics | RCV000621114 | SCV000736690 | uncertain significance | Cardiovascular phenotype | 2019-12-03 | criteria provided, single submitter | clinical testing | The p.M349T variant (also known as c.1046T>C), located in coding exon 10 of the MYH7 gene, results from a T to C substitution at nucleotide position 1046. The methionine at codon 349 is replaced by threonine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (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 variant has been identified in hypertrophic cardiomyopathy (HCM) cohorts (Mattivi CL et al. Circ Genom Precis Med, 2020 10;13:453-459; Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37). This alteration has also been detected in trans with a second, de novo MYH7 alteration in a child with sudden cardiac arrest and HCM, while family members who had only the p.M349T alteration were reportedly unaffected (Jeschke B et al. Hum Genet. 1998;102:299-304). Another alteration affecting the same amino acid, p.M349V (c.1045A>G), has been reported in association with HCM and dilated cardiomyopathy (DCM), but evidence of pathogenicity is currently limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is poorly 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. |
| Invitae | RCV000694881 | SCV000823346 | uncertain significance | Hypertrophic cardiomyopathy | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 349 of the MYH7 protein (p.Met349Thr). This variant is present in population databases (rs121913640, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) and an early onset form of HCM (PMID: 9544842, 18761664, 32894683). ClinVar contains an entry for this variant (Variation ID: 14094). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. |
| Color Diagnostics, |
RCV001188427 | SCV001355485 | uncertain significance | Cardiomyopathy | 2023-06-15 | criteria provided, single submitter | clinical testing | This missense variant replaces methionine with threonine at codon 349 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: 9544842, 18761664, 24793961, 32894683). In one family, this variant was reported in compound heterozygous state with another de novo pathogenic MYH7 variant in an individual affected with early-onset hypertrophic cardiomyopathy (PMID: 9544842, 18761664). 6 relatives of this individual were asymptomatic heterozygous carriers for this variant. This variant has been identified in 1/31328 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. |
| Fulgent Genetics, |
RCV002490370 | SCV002786504 | 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 | 2022-02-15 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000015150 | SCV000035407 | pathogenic | Hypertrophic cardiomyopathy 1 | 1998-03-01 | no assertion criteria provided | literature only |