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

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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	2023-03-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as 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). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181401). This missense change has been observed in individuals with hypertrophic cardiomyopathy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 247 of the MYH7 protein (p.Phe247Cys).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507832	SCV000604367	likely pathogenic	not specified	2018-05-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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.
Ambry Genetics	RCV000620575	SCV000737345	pathogenic	Cardiovascular phenotype	2021-07-23	criteria provided, single submitter	clinical testing	The p.F247C pathogenic mutation (also known as c.740T>G), located in coding exon 7 of the MYH7 gene, results from a T to G substitution at nucleotide position 740. The phenylalanine at codon 247 is replaced by cysteine, an amino acid with highly dissimilar 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 detected in individuals with hypertrophic cardiomyopathy (HCM) (Ho CY et al. Circulation. 2018 10;138(14):1387-1398; Ambry internal data; Invitae pers. comm.). Based on internal structural assessment, this variant disrupts the local structure of the myosin head at the interface between the N and C-terminal domains (Winkelmann DA et al. Nat Commun, 2015 Aug;6:7974). Another alteration affecting the same amino acid, p.F247L (c.739T>C), has been reported in association with HCM (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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