ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.740T>G (p.Phe247Cys) (rs730880922)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507832 SCV000604367 likely pathogenic not specified 2018-05-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620575 SCV000737345 likely pathogenic Cardiovascular phenotype 2017-12-22 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,Well-characterized mutation at same position,Structural Evidence
GeneDx RCV000158881 SCV000208816 pathogenic not provided 2011-12-09 criteria provided, single submitter clinical testing This mutation is denoted p.Phe247Cys (F247C) at the protein level and c.740 T>G at the cDNA level. The Phe247Cys mutation in the MYH7 gene has not been published previously as a disease-causing mutation or a benign polymorphism, to our knowledge. Phe247Cys results in a non-conservative amino acid substitution of a non-polar Phenylalanine with a neutral, polar Cysteine. Mutations affecting the same residue (Phe247Leu) or nearby residues (Phe244Leu, Lys246Gln, Arg249Gln, His251Asn) have been reported in association with HCM, further supporting the functional importance of this residue and this region of the protein. Furthermore, Phe247Cys was not detected in 640 alleles from control individuals of various ethnicities tested at GeneDx, indicating it is not a common benign variant. The variant is found in HCM panel(s).
Invitae RCV000225905 SCV000284294 pathogenic Hypertrophic cardiomyopathy 2017-08-31 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 247 of the MYH7 protein (p.Phe247Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 181401). 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). A different missense substitution at this codon (p.Phe247Leu) has been determined to be pathogenic (PMID: 19150014, 22765922, 20594303). This suggests that the phenylalanine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000507832 SCV000731452 uncertain significance not specified 2017-01-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe247Cys variant in MYH7 has not been previously reported in individuals with cardiomyop athy, but has been reported in ClinVar (Variation ID: 181401). This variant was absent from large population studies. Of note, this variant lies in the head reg ion of the protein. Missense variants in this region have been reported and stat istically indicated to be more likely to cause disease (Walsh 2016). Phenylalani ne (Phe) at position 247 is highly conserved in mammals and across evolutionaril y distant species and the change to cysteine (Cys) was predicted to be pathogeni c using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical s ignificance of the p.Phe247Cys variant is uncertain.

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