ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1358G>A (p.Arg453His) (rs397516101)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000195545 SCV000564415 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1358G>A (p.Arg453His) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:20428263; PMID:15858117; PMID:20800588; PMID:21835320; PMID:22429680; Partners LMM ClinVar SCV000059369.5; Invitae ClinVar SCV000253816.4; SHaRe consortium, PMID: 30297972). This variant was been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:20428263). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.1357C>T p.Arg453Cys; ClinVar Variation ID 14089). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PM6; PP3
GeneDx RCV000158800 SCV000208735 pathogenic not provided 2012-03-12 criteria provided, single submitter clinical testing The Arg453His mutation in the MYH7 gene has been previously reported in association with HCM. Haluza et al. observed Arg453His in a single individual with childhood onset obstructive HCM and no family history of heart disease (Haluza et al. 2001). Arg453His was also observed by Yu et al. in a single individual from a cohort of Australian patients with familial hypertrophic cardiomyopathy (Yu et al. 2005). Although Arg453His results in a conservative amino acid substitution of one positively-charged amino acid with another, this change occurs at a position that is highly conserved throughout evolution. In addition, in silico analysis predicts Arg453His to be probably damaging to the protein structure/function (Adzhubei IA et al, 2010). Mutations at the same codon (Arg453Cys, Arg453Leu, Arg453Ser) and nearby codons (Lys450Glu, Lys450Thr) have been reported in association with HCM, further supporting the functional importance of this residue and this region of the protein. The NHLBI ESP Exome Variant Server reports Arg453His was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s).
Invitae RCV000195545 SCV000253816 pathogenic Hypertrophic cardiomyopathy 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 453 of the MYH7 protein (p.Arg453His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (PMID: 15858117, 22429680, 20800588, 21835320, 23140321, 24093860, 27247418).  It has been identified as arising de novo in an individual affected with HCM (PMID: 20428263) in addition to a second pathogenic allele in the MYH7 gene in this individual., which suggests that this c.1358G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 42838). 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.Arg453Cys) has been determined to be pathogenic (PMID: 8655135, 12975413, 11133230, 27247418, 23283745, 23798412, 17351073, 24344137). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000195545 SCV000059369 likely pathogenic Hypertrophic cardiomyopathy 2013-01-12 criteria provided, single submitter clinical testing The Arg453His variant has been reported in 5 individuals with HCM (Haluza 2001, Yu 2005, Millat 2010, Olivotto 2011, Santos 2012) and in one African American in dividual with HCM previously tested by our laboratory (LMM unpublished data). I n one individual, the variant had occurred ?de novo? but the presence of a secon d, pathogenic MYH7 variant (Arg403Trp) left the clinical significance of the Arg 453His variant uncertain (Haluza 2001). This variant has not been identified in large European American and African American populations by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS/), which is consistent with a p athogenic role. However, we cannot exclude that it may be common in other popula tions. Arginine (Arg) at position 453 is conserved in evolution and 3 other vari ants at that position have been reported (Arg453Cys, Arg453Ser, Arg453Leu), sugg esting that a change would not be tolerated. The Arg453His variant was also pred icted to be pathogenic using a computational tool, which was validated by our la boratory using a set of cardiomyopathy variants with well-established clinical s ignificance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely to be pathogenic, th ough additional studies are required to fully establish its clinical significanc e.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000201462 SCV000256123 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845295 SCV000987326 likely pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158800 SCV000280299 likely pathogenic not provided 2015-03-24 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.Arg453His (c.1358G>A) in the MYH7 gene. Given this variant is seen in several unrelated families with HCM in the literature, and its rarity in the general population, we consider this variant to be likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 7 unrelated cases of HCM (not including this patient's family). It is currently listed in ClinVar, where the Laboratory for Molecular Medicine (LMM) classifies it as “likely pathogenic”: ClinVar accession RCV000035718.2. Haluza et al. (2001) reported the variant in a 23 yo male with obstructive HCM who was found to be compound heterozygous for this variant and MYH7 p.Arg403Trp (which we consider very likely disease causing). Interestingly, this p.Arg453His variant was found to be de novo in that patient, making the significance of p.Arg453His somewhat uncertain at the time. The authors do discuss the male patient’s early presentation, which consisted of multiple syncopal events by the age of 17, and at 23 years of age development of heart failure. He reportedly had no family history of HCM. Yu et al. (2005) reported this variant in one Australian patient with HCM. 100 ethnicity matched controls were screened. Millat et al (2010) reported this variant in a patient with HCM. Ancestry is not specified but the authors are from a French group, and they screened French control chromosomes when evaluating novel variants as part of their study. Teirlinck et al 2012 does report this variant in an individual with HCM, but it is unclear if this represents the same individual as reported by Millat et al 2010 (same authors and appears to be the same French cohort). Olivotto et al. (2011) reported this variant in a 15 yo female patient with HCM. Santos et al (2012) identified this variant in a Portuguese patient with HCM, who also was identified with another missense variant in MYH7: p. c.2644 C > G; p.Gln882Glu. The authors state that all patients with multiple mutations had septal hypertrophy and a family history of HCM; but the data for this specific patient is not available in their table 2 (which describes this info on the cohort). The authors screened 100 controls. Marsiglia et al (2013) identified this variant in a Brazilian patient with HCM. Finally, the Laboratory for Molecular Medicine reports that they have seen this variant in one African American individual with HCM previously tested by their laboratory (LMM, unpublished data- ClinVar). There is no available segregation data on the variant. In silico analysis with Mutation Taster and PolyPhen-2 predicts the variant to be damaging. The Arginine at codon 453 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Arg453Cys and Arg453Leu) and nearby codons (p.Lys450Glu, p.Lys450Thr). There is strong evidence supporting the pathogenicity of p.Arg453Cys (considered very likely disease causing by our team), providing additional evidence of the functional importance of this region. In total the variant has not been seen in approximately 60,200 published controls and individuals from publicly available population datasets. There is no variation at codon 453 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 9/9/15). Note that this dataset does not match the patient's ancestry (India). There is also no variation at codon 473 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent (as of 9/3/2015).

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