ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2105T>A (p.Ile702Asn) (rs397516132)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000628958 SCV000059414 likely pathogenic Hypertrophic cardiomyopathy 2014-02-06 criteria provided, single submitter clinical testing The Ile702Asn variant in MYH7 has been reported in 1 individual with DCM as well as 5 affected relatives (2 with DCM and 3 with HCM), with the possibility that the DCM in this family resulted from end-stage HCM (Bishara 2008, LMM unpublishe d data, pers. comm.). The variant was absent from large population studies and was predicted to be pathogenic using a computational tool clinically validated b y our laboratory. This tool's pathogenic prediction is estimated to be correct 9 4% of the time (Jordan 2011).In summary, this variant is likely to be pathogenic , though additional studies are required to fully establish its clinical signifi cance.
GeneDx RCV000158508 SCV000208443 likely pathogenic not provided 2014-05-23 criteria provided, single submitter clinical testing p.Ile702Asn (ATC>AAC): c.2105 T>A in exon 19 of the MYH7 gene (NM_000257.2). An I702N variant that is likely pathogenic was identified in the MYH7 gene. I702N in the MYH7 gene has been reported in an individual with HCM (Zou et al., 2013). I702N results in a non-conservative amino acid substitution of a non-polar Isoleucine with a polar Asparagine at a position that is well conserved across species. Consequently, in silico analysis predicts I702N is damaging to the protein structure/function. Mutations in nearby residues (N696S, V698A, C705W, P710H, P710R, R712L) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, the I702N variant was not observed in approximately 6,500 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, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM,HCM,CARDIOMYOPATHY panel(s).
Invitae RCV000628958 SCV000749867 likely pathogenic Hypertrophic cardiomyopathy 2018-01-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 702 of the MYH7 protein (p.Ile702Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25611685).  ClinVar contains an entry for this variant (Variation ID: 42880). 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). 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). A different missense substitution at this codon (p.Ile702Val) has been determined to be pathogenic (PMID: 23283745, 27247418, 27532257). This suggests that the isoleucine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193366 SCV001362130 likely pathogenic Cardiomyopathy 2019-08-12 criteria provided, single submitter clinical testing Variant summary: MYH7 c.2105T>A (p.Ile702Asn) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Cardiomyopathy (Bishara_2008, Walsh_2017, Alfares_2015), which includes one family showing segregation with disease (Bishara_2008). These data indicate that the variant is likely to be associated with disease. Another missense change at this codon, p.I702V, has also been documented as pathogenic in the literature (PMID # 23283745, 27247418, 27532257) suggesting the importance of this residue in MYH7 protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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