ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4259G>A (p.Arg1420Gln) (rs397516207)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000200190 SCV000059549 likely pathogenic Hypertrophic cardiomyopathy 2017-12-08 criteria provided, single submitter clinical testing The p.Arg1420Gln variant in MYH7 has been identified in 7 individuals with HCM a nd segregated with disease in 3 affected relatives (Bortot 2011, Wang 2014, Lope s 2015, Murphy 2016, Walsh 2016, LMM unpublished data). This variant was also se en in one individual in a sudden cardiac death cohort (Lahrouchi 2017). This var iant was absent from large population studies. Arginine (Arg) at position 1420 i s highly conserved in mammals and across evolutionarily distant species and the change to glutamine (Gln) was predicted to be pathogenic using a computational t ool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Additionally, a differen t disease-causing substitution has been reported at this position (p.Arg1420Trp) suggesting that changes at this position may not be tolerated. In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Arg1420Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PM2 , PP1, PM5, PP3, PS4_Moderate (Richards 2015).
GeneDx RCV000035898 SCV000208582 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing The R1420Q variant in the MYH7 gene has been reported in association with HCM (Bortot et al., 2011; Lopes et al., 2015; Murphy et al., 2016). Initially, Bortot et al. (2011) reported this variant one individual with HCM and described as segregating with disease in additional affected family members; however, detailed information was not provided. Additionally, this variant has been reported in one patient with sudden arrhythmic death syndreom (SADS) (Lahrouchi et al., 2017). The R1420Q variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals. The R1420Q variant is not observed in large population cohorts (Lek et al., 2016). The R1420Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, a missense variants in the same residue (R1420W) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000200190 SCV000253684 likely pathogenic Hypertrophic cardiomyopathy 2015-04-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1420 of the MYH7 protein (p.Arg1420Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (PMID: 21817903), and is not present in population databases. ClinVar contains entries for this variant which indicate that it was observed in an isolated hypertrophic cardiomyopathy case (RCV000158647) and was reported to segregate with hypertrophic cardiomyopathy in one family (RCV000035898). A different missense substitution at this codon (p.Arg1420Trp) has been reported in several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 24055113, 23283745 ), indicating that the arginine residue may be critical for protein function. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be pathogenic. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, this is a rare sequence change that affects an amino acid residue which is important for protein function and has been reported to segregate with disease in one family. For these reasons it has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770479 SCV000901922 uncertain significance Cardiomyopathy 2016-07-04 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000035898 SCV000927243 likely pathogenic not provided 2017-04-30 criteria provided, single submitter clinical testing

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