ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2429G>A (p.Arg810His) (rs375675796)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250821 SCV000320671 likely pathogenic Cardiovascular phenotype 2018-03-22 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,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CSER_CC_NCGL; University of Washington Medical Center RCV000148677 SCV000190401 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000730623 SCV000858374 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing
GeneDx RCV000730623 SCV000208092 uncertain significance not provided 2018-10-10 criteria provided, single submitter clinical testing The R810H variant in MYBPC3 has been reported in multiple individuals with HCM (Nanni et al., 2003; Van Driest et al., 2004; Kaski et al., 2009; Maron et al., 2011; Roncarati et al., 2011; Ho et al., 2013; Coppini et al., 2014; Liu et al., 2015; Rubattu et al., 2016). Nanni et al. (2003) first identified R810H in two unrelated patients diagnosed with HCM. The first patient was homozygous for the R810H variant and presented with a severe hypertrophy and a positive family history, while the second patient harbored another pathogenic variant in the MYBPC3 gene and presented with a moderate hypertrophy without obstruction (Nanni et al., 2003). Maron et al. (2011) reported that this variant segregated with disease in two affected adults from the same family. More recently, Liu et al. (2015) identified the R810H variant in a patient diagnosed with HCM at 20 years old who also harbored a second missense variant in the MYBPC3 gene. Both variants were absent in the patient's asymptomatic mother and daughter indicating they are arranged in cis and were either paternally inherited or occurred de novo (Liu et al., 2015). This variant has also been observed in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was often the only variant identified by gene panel analysis. The R810H variant is observed in 4/66634 (0.01%) alleles from individuals (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R810H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000537026 SCV000623555 uncertain significance Hypertrophic cardiomyopathy 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 810 of the MYBPC3 protein (p.Arg810His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs375675796, ExAC 0.006%). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (HCM); however, in at least one of them the individual carried a different variant that explained the disease (PMID: 12951062, 27600940, 15519027, 26090888, 27483260, 15936968). It has also been reported in the homozygous state in an individual with HCM and left ventricular outflow tract obstruction (LVOTO) (PMID: 12951062). ClinVar contains an entry for this variant (Variation ID: 42620). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035488 SCV000059138 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg810His variant in MYBPC3 has been reported in 1 homozygous and 16 heterozygous individ uals with HCM and segregated with disease in 3 affected relatives from 3 familie s (Nanni 2003, Van Driest 2004, Van Driest 2005, Kaski 2009, Roncarati 2011, Mar on 2011, LMM unpublished data). Of the 17 probands with this variant, 3 carried another likely disease causing variant, raising the possibility that this varian t may have a mild effect and/or may require other genetic or environmental facto rs to cause disease. The p.Arg810His variant has been identified in 11/11164 Eu ropean chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs375675796). Computational prediction tools and conserva tion analysis suggest that the p.Arg810His variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, while there is some suspicion for a pathogenic role, the clinical significan ce of the p.Arg810His variant is uncertain.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000201483 SCV000256161 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000035488 SCV000280237 uncertain significance not specified 2015-07-29 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. MYBPC3 p.Arg810His Seen in at least 29 presumably unrelated cases of HCM (5 published, 24 unpublished). In 11 of 27 cases who had sequencing of at least MYH7, MYBPC3, and TNNT2 had another variant (10 had another sarcomeric variant, 1 had an FRDA variant). -There is weak segregation data. In three families an additional affected relative carried Arg810His. In two other families an additional affected relative carried Arg810His in additional to another variant. -In total, the variant has been seen in 4 of ~60,751 individuals from published controls and publicly available datasets that approximate the general population. Nanni L et al. (2003) reported this variant in two patients diagnosed with HCM cared for in Rome who underwent analysis of MYH7, MYBPC3, and TNNT2. One of the two patients was homozygous for the variant and presented with dyspnea at age 39. He also showed severe hypertrophy (IVS 32 mm) and a LVOTO of 50 mmHg. Authors report a positive family history but no evidence was provided, and reported that he came from a closed community of a little town that may explain the homozygous genotype. The other patient, who also carries a second variant (MYBPC3-Arg820Gln) had moderate non-obstructive hypertrophy. Arg820Gln has conflicting classifications in ClinVar: LMM – likely pathogenic, GeneDx – Pathogenic, and Molecular Genetics Diagnostic Laboratory – VUS (at the time of our review). Ackerman’s group reported this variant in a patient with HCM. This cohort included 389 unrelated patients with HCM who were assessed for variants in eight HCM-associated genes (van Driest et al., (2004). The patient did not have any other sarcomere variants. However, the same group later reported a novel variant in FRDA gene (Arg40Cys) associated with Fredeich ataxia in this patient (Van Driest S et al. 2005). They searched for variants in FRDA in 389 patients with clinical HCM who were previously assessed for variants in eight HCM-associated genes. None of the 389 patients had a clinical diagnosis of Friedreich ataxia and the FRDA trinucleotide repeat expansion size was normal on both alleles. The double heterozygous patient was diagnosed with unequivocal and unexplained cardiac hypertrophy at 12 years of age but remained clinically asymptomatic until age 32. He underwent ICD placement due to recurrent ventricular fibrillation and received multiple appropriate shocks. He went on to develop left ventricular systolic dysfunction (ejection fraction 35%). No evidence of disease was found in any of his living first degree relatives. The authors propose that the combination of the MYBPC3 variant and the FRDA variant lead to his HCM. They argued that the young diagnosis, arrhythmic burden, and heart failure are all atypical for MYBPC3-associated HCM. They note no neurological involvement. McKenna’s group reported this variant in one out of 79 HCM patients with diagnosis under 13 years old recruited in the UK (Kaski et al. 2009). No individual phenotype, genotype or ancestry information was reported. They sequenced 9 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, and TNNC1), the genes encoding desmin (DES), and the gamma-2 subunit of AMP kinase (PRKAG2). The paper states that a total of 5/79 patients were double heterozygotes in MYBPC3 gene, but it doesn’t mention which variants in this gene were found in these individuals. Therefore, the variant zygosity of this patient is equivocal. Maron and Semsarian reported this variant in two brothers with HCM (Maron et al 2011). One of the brothers has two unaffected daughters (aged 10 and 12), who are hetrozygous for this variant but had normal echocardiograms at that time. See pedigree below for details. They do not note how many genes were analyzed, ancestry, or where the cases were recruited (though most likely Maron and Semsarian’s clinics). 4 sites have reported patients with this variant in SHaRe registry. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging and SIFT predicts the variant to be deleterious. The arginine at codon 810 is highly conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (R810L and R810Q) and nearby codons (G805S; K811R). Total the variant has been seen in 4 of ~60,751 individuals from published controls and publicly available datasets that approximate the general population. The variant was reported online in 4 of 60,259 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 22nd, 2015). Specifically, the variant was observed in 4 of ~33,317 European individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population; others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). This variant is currently listed in dbSNP: rs375675796. The variant was not observed in the following published control samples: Nanni (2003) did not report this variant in 100 control individuals, Van Driest (2004) did not report it in 200 control individuals, Roncarati (2011) did not report it in 192 controls.

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