14-23429004-C-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PP3PM6PM5PM1PM2
This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA010639/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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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 -
Classified as pathogenic in ClinVar by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564415.2; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15858117, 27247418, 27532257, 20800588, 29300372, 23140321, 28420666, 23074333, 21835320, 21310275, 8655135, 20428263, 22429680, 29907873, 31006259, 31321302, 33673806) -
PS4, PM2, PM5, PM6, PP3 -
Hypertrophic cardiomyopathy Pathogenic:3
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 453 of the MYH7 protein (p.Arg453His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15858117, 20800588, 21835320, 22429680, 23140321, 24093860, 27247418). This missense change has been observed to co-occur in individuals with a different variant in MYH7 that has been determined to be pathogenic (PMID: 20428263), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 42838). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg453 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8655135, 11133230, 12975413, 17351073, 23283745, 23798412, 24344137, 27247418). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
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. -
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 -
Primary familial hypertrophic cardiomyopathy Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The p.R453H pathogenic mutation (also known as c.1358G>A), located in coding exon 12 of the MYH7 gene, results from a G to A substitution at nucleotide position 1358. The arginine at codon 453 is replaced by histidine, an amino acid with highly similar 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 alteration has been reported in multiple individuals from hypertrophic cardiomyopathy (HCM) cohorts (Yu B et al. J. Clin. Pathol., 2005 May;58:479-85; Millat G et al. Clin. Chim. Acta, 2010 Dec;411:1983-91; Olivotto I et al. J. Am. Coll. Cardiol., 2011 Aug;58:839-48; Marsiglia JD et al. Am. Heart J. 2013 Oct;166(4):775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203; Kelly MA et al. Genet. Med., 2018 03;20:351-359). This alteration was reported to occur de novo in an individual with early onset HCM who also had a second MYH7 mutation (Haluza R et al. Exp Clin Cardiol, 2001;6:223-7). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -
Hypertrophic cardiomyopathy 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at