ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.619A>C (p.Lys207Gln) (rs727504273)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766406 SCV000208687 uncertain significance not provided 2018-09-05 criteria provided, single submitter clinical testing The K207Q variant of uncertain significance in the MYH7 gene has been reported in association with HCM in one large family (Mohiddin et al., 2003; Alpert et al., 2005). The proband, who was diagnosed with HCM at age 47, was reported to be homozygous for the K207Q variant. Of the proband's nine relatives who were heterozygous for K207Q, only one had evidence of HCM (Mohiddin et al., 2003; Alpert et al., 2005). This 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 K207Q variant is not observed in large population cohorts (Lek et al., 2016). The K207Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Kelly et al., 2018). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America RCV000780519 SCV000917846 likely pathogenic Primary familial hypertrophic cardiomyopathy 2018-10-22 criteria provided, single submitter clinical testing Variant summary: MYH7 c.619A>C (p.Lys207Gln) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) and is found in a surface loop that spans the entrance to the ATP-binding pocket (Alpert 2005). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246666 control chromosomes (gnomAD and publication data). c.619A>C has been reported in the literature in a family with a homozygous individual affected with Hypertrophic Cardiomyopathy (HCM) that later seemed to transition into Dilated Cardiomyopathy (DCM); although the variant was found in several family members in heterozygosity, only one of them was affected by HCM (Mohiddin 2003, Alpert 2005). The variant was also reported to be found in HCM patient cohorts in heterozygous state (Bos 2014, Homburger 2016, Walsh 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, characterizing skeletal muscle myosin from biceps muscles of the homozygous patient, however, this study does not allow convincing conclusions about the variant effect (Alpert 2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000231809 SCV000284290 likely pathogenic Hypertrophic cardiomyopathy 2017-11-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 207 of the MYH7 protein (p.Lys207Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous state in an individual affected with hypertrophic cardiomyopathy (HCM), although some family members carrying this variant in the heterozygous state did not develop HCM (PMID: 12820698, 15528230). It has also been reported in the heterozygous state in three other unrelated individuals affected with HCM (PMID: 27247418, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 177674). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. 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). In summary, this variant is a rare missense change with uncertain impact on protein function and it is located in a region of the protein where other deleterious variants have been observed. It has been reported in multiple affected individuals, however, in one family several variant carriers were not affected. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154271 SCV000203930 uncertain significance not specified 2013-03-06 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000154271 SCV000280374 uncertain significance not specified 2014-07-24 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Lys207Gln (c.619 A>C) in MYH7 (NM_000257.2) We have seen this in a patient with early onset HCM, severe LVH, who also carries p.Ile736Val (c.2206 A>G) in MYH7 (NM_000257.2) (phase not known). As reviewed below, we classify both of these variants as variants of uncertain significance, probably disease causing. They are good candidates, either individually or in combination, for the cause of his cardiomyopathy, however we cannot currently conclude with sufficient confidence that they are in fact the causative variants. The variant has been seen in at least two unrelated cases of HCM (not including this patient's family). Mohiddin et al (2003) reported a patient with HCM who was homozygous for this variant. The patient was from an NIH cohort of 100 HCM patients who had analysis of just MYH7. HCM was diagnosed at 47 years of age and at 64yo the maximal wall thickness was 2.1 cm, at the apex. History included syncope, appropriate shocks from his ICD, chronic atrial fibrillation, eventual left ventricular dilatation and heart failure class III symptoms. A sibling was a heterozygote and got diagnosed with HCM at 80yo with a thickness of 3.5 cm. Three children in their 40s were heterozygotes and had normal echos. Three grandchildren <16 yo Were also heterozygotes and had normal echos. Several heterozygotes had resting sinus bradycardia. Ancestry was not reported. Consanguinity was denied and haplotype analysis was not reported. The same case was included in a later publication by this group (Alpert et al 2005). Dr. Ackerman's group reported the variant in one patient in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo. We have not seen this variant before. It is not currently listed in ClinVar (as of July 3rd, 2014). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.551). The lysine at codon 207 is conserved across all mammalian cardiac myosins, regardless of isoform (Alper et al 2002). Other variants have been reported in association with disease at nearby codons (Ala199Val, Ala200Thr, Ile201Thr, Arg204His, Ser205Cys, Q209E, Pro211Leu, Gly214Asp, Leu216Val per GeneDx report, referencing HGMD). In total the variant has not been seen in 6800 published controls and individuals from publicly available population datasets. There is no variation at codon 207 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). There is also no variation at this codon listed in dbSNP (as of July 3rd, 2014). The variant was not observed in the following published control samples: 100 (Mohiddin et al 2003), 200 (Bos et al 2014).

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