ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln) (rs587782962)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000529602 SCV000564442 likely pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.3158G>A (p.Arg1053Gln) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy, the majority of whom are of Finnish ancestry (PS4; PMID:15556047; PMID:24888384; PMID:27532257; Partners LMM ClinVar SCV000203956.4). This variant segregated with disease in 5 affected individuals in a family of Finnish ancestry (PP1_Moderate; PMID:15556047). This variant was identified in 0.1% (9/6604) of Finnish chromosomes by ExAC, but was absent from all other populations (PM2; Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PP1_Moderate; PP3
Blueprint Genetics RCV000143923 SCV000188800 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000529602 SCV000203956 pathogenic Hypertrophic cardiomyopathy 2014-05-08 criteria provided, single submitter clinical testing The Arg1053Gln variant in MYH7 has been reported in 1 individual with a dilated left ventrical and impaired systolic function, and was present in 5 additional a ffected family members with clinical features of septal HCM (Karkkainen 2004). I n addition, it has been identified by our laboratory in 1 individual with HCM an d family history of SCD. The variant was absent from large population studies. Arganine (Arg) at position 1053 is highly conserved in evolution and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool cli nically validated by our laboratory. This tool's pathogenic prediction is estima ted to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic ( bas ed upon segregation studies and absence from controls.
GeneDx RCV000158590 SCV000208525 pathogenic not provided 2014-01-19 criteria provided, single submitter clinical testing The R1053Q mutation in the MYH7 gene has been reported previously in five individuals with cardiomyopathy from two generations of one family from eastern Finland (Karkkainen S et al., 2004). R1053Q was not present in 150 healthy control subjects in this study (Karkkainen S et al., 2004), and was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R1053Q results in a semi-conservative amino acid substitution of positively charged Arginine with a neutral Glutamine at a position that is highly conserved across species. Consequently, in silico analysis predicts R1053Q is damaging to the protein structure/function. Additionally, mutations in nearby residues (R1045H, R1045C, A1051V, E1056D, G1057D) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. The variant is found in HCM panel(s).
Invitae RCV000529602 SCV000623690 pathogenic Hypertrophic cardiomyopathy 2018-05-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1053 of the MYH7 protein (p.Arg1053Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782962, ExAC 0.1%). This variant is clearly defined as a hypertrophic cardiomyopathy causative allele in individuals of Finnish ancestry (PMID: 27460395). It has been observed in many unrelated individuals and families with hypertrophic cardiomyopathy (PMID: 15556047, 20624503, 24888384, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 155814). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000621026 SCV000739917 likely pathogenic Cardiovascular phenotype 2017-07-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation

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