ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000537026 SCV000059138 likely pathogenic Hypertrophic cardiomyopathy 2020-06-15 criteria provided, single submitter clinical testing The p.Arg810His variant in MYBPC3 has been identified in the heterozygous state in >35 individuals with HCM and segregated with disease in 3 affected relatives from 3 families (Nanni 2003 PMID: 12951062, Van Driest 2004 PMID: 15519027, Van Driest 2005 PMID: 15936968, Kaski 2009 PMID: 20031618, Roncarati 2011 PMID: 21302287, Maron 2011 PMID: 21185001, Rubattu 2015 PMID: 27483260, Walsh 2017 PMID: 27532257, Invitae pers. comm., Ambry pers. comm., GeneDx pers. comm., LMM data). It was also identified in 9 individuals with additional disease-causing variants in cardiomyopathy related genes (Nanni 2003 PMID: 12951062, Van Driest 2005 PMID: 15936968, Liu 2015 PMID: 26090888, Ambry pers. comm., GeneDx pers. comm., LMM data). On average, these individuals with a second variant had an earlier age of onset than the heterozygous individuals. This variant has also been identified in 0.009% (11/112984) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported by other clinical laboratories in ClinVar (Variation ID# 42620). Computational prediction tools and conservation analyses are consistent with pathogenicity. Based on criteria selected, this variant would be classified as uncertain significance; however, the available evidence is sufficiently borderline and the earlier age of onset in individuals with additional disease-causing variants provided additional evidence not accounted for by the current rules. Therefore, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP1, PP3, with adjustment based on clinical judgment.
GeneDx RCV000730623 SCV000208092 uncertain significance not provided 2021-08-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 42620; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33558530, 33782553, 30847666, 15115610, 21415409, 25351510, 28615295, 28790153, 27483260, 12951062, 21185001, 26090888, 25524337, 21302287, 20031618, 25335496, 18761664, 23549607, 25637381, 23299917, 15936968, 15519027, 27532257, 27600940)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201483 SCV000256161 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250821 SCV000320671 likely pathogenic Cardiovascular phenotype 2019-05-24 criteria provided, single submitter clinical testing The p.R810H variant (also known as c.2429G>A), located in coding exon 25 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2429. The arginine at codon 810 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM), though in some cases, a second alteration was also detected or clinical details were limited (Coppini et al. J Am Coll Cardiol. 2014;64(24):2589-600; Roncarati et al. Cell Physiol. 2011;226(11):2894-900; Kaski et al. Circ Cardiovasc Genet. 2009;2(5):436-41; Van Driest et al. Mol & Genet Metab. 2005;85(4):280-5; Van Driest et al. J Am Coll Cardiol. 2004;44(9):1903-10; Liu et al. Sci Rep. 2015;5:11411; Lopes et al. Heart. 2015;101(4):294-301). One study reported this alteration in the homozygous state in an individual with a more severe presentation, and an additional publication reported this alteration to co-segregate with disease in two siblings (Nanni et al. Biochem Biophys Res Commun. 2003;309(2):391-8; Maron et al. Am J Cardiol. 2011;107(4):604-8). In addition, another alteration affecting the same amino acid, p.R810L (c.2429G>T), has also been reported in association with HCM (Millat et al. Eur J Med Genet. 2010;53(5):261-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000537026 SCV000623555 uncertain significance Hypertrophic cardiomyopathy 2020-07-30 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000730623 SCV000858374 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV001184543 SCV001350552 likely pathogenic Cardiomyopathy 2020-10-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 810 in the fibronectin type 3 domain of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant had a 44% prolonged MyBPC protein half-life compared to wild-type (PMID: 32841044). However, clinical relevance of this observation is not clear. This variant has been reported in around 30 individuals affected with hypertrophic cardiomyopathy (PMID: 12951062, 15519027, 15936968, 20031618, 20624503, 21185001, 21302287, 25524337, 26090888, 27483260, 27532257, 27600940). This variant has also been reported in two individuals with hypertrophic cardiomyopathy in one family (PMID: 21185001). This variant has been identified in 12/249184 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CSER _CC_NCGL, University of Washington RCV000148677 SCV000190401 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
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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