ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2618C>A (p.Pro873His) (rs371401403)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035516 SCV000059166 uncertain significance not specified 2018-11-05 criteria provided, single submitter clinical testing The p.Pro873His variant in MYBPC3 has been reported in the heterozygous state in 2 individuals with HCM and 2 individuals with DCM (Ingles 2005, Maron 2012, van Spaendonck-Zwarts 2013, LMM data). It segregated with DCM or HCM in 4 affected individuals from 1 family (LMM data). It has also been identified in the homozyg ous state in an individual with HCM with no reported family history of disease ( Nanni 2003) and in an additional individual with severe HCM whose brother was al so homozygous for the variant and had mild symptoms (Kissopoulou 2018). Several reportedly unaffected family members (ages 10-54) were heterozygous for the vari ant (Kissopoulou 2018). This variant has also been reported by other clinical la boratories in ClinVar (Variation ID: 30143) and has also been identified in 0.01 % (14/98008) European chromosomes, including 1 homozygote, by gnomAD (http://gno mad.broadinstitute.org/). Computational prediction tools and conservation analys is suggest that the p.Pro873His variant may impact the protein. In summary, due to conflicting evidence, the clinical significance of the p.Pro873His variant is uncertain. ACMG/AMP Criteria applied: PP1, PP3, PS4_Supporting, BS1_Supporting.
GeneDx RCV000766358 SCV000208112 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing The P873H variant of uncertain significance in the MYBPC3 gene has been previously reported in the heterozygous state in association with cardiomyopathy (Ingles et al., 2005; Maron et al., 2012; vanSpaendonk-Zwarts et al., 2013); however, segregation data were not provided, and the majority of these individuals were also found to harbor another variant in the MYBPC3 gene. In addition, Nanni et al. (2003) reported one individual with moderate/severe hypertrophy and obstruction of the left ventricular outflow tract who was homozygous for the P873H variant; this homozygous result was thought to be due to consanguinity, and there was no reported family history of HCM. Furthermore, P873H has been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members.Furthermore, the P873H variant is observed in 13/97288 (0.01%) alleles from individuals of European (non-Finnish) background, including one homozygous individual, in large population cohorts (Lek et al., 2016). Nevertheless, this variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Lastly, a different amino acid change at the same resdiue (P873L) has been reported in one individual with left ventricular non-compaction (Probst et al., 2011); however, the pathogenicity of this variant has not been definitively determined. Therefore, this variant lacks segregation data and functional evidence, which would further clarify its pathogenicity.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201917 SCV000256664 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-07-02 criteria provided, single submitter research The MYBPC3 Pro873His variant has been reported in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0003 (13 of 39424 in the European Finnish population). We have identified the MYBPC3 Pro873His variant in an HCM proband where one additional MYBPC3 (Asp745Gly) variant of uncertain significance has also been observed (Ingles J., et al 2005). This proband was diagnosed with HCM at 18 years, has asymmetric hypertrophy with a maximal wall thickness of 30mm and has received appropriate therapy from his ICD. Segregation analysis was limited but showed this MYBPC3 Pro873His variant to be present in one other affected family member (who also carries the additional MYBPC3 Asp745Gly variant). In addition, this variant has been identified in one HCM individual who was homozygous for the variant (Nanni L., et al 2003) and has also been identified in one DCM patient (Spaendonck-Zwarts K., et al 2013). Predictions from in silico tools (SIFT, PolyPhen2, MutationTaster) are supportive of a deleterious effect. However, due to co-occurrence in our proband with an additional MYBPC3 variant, limited familial data, and insufficient evidence, we classify this MYBPC3 Pro873His variant as one of "uncertain significance".
Invitae RCV000474002 SCV000546492 uncertain significance Hypertrophic cardiomyopathy 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 873 of the MYBPC3 protein (p.Pro873His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases, including one homozygous individual (rs371401403, ExAC 0.03%). This variant has been observed in the homozygous state in several individual with hypertrophic cardiomyopathy (PMID: 12951062, 29663722), and was observed in the heterozygous state in several unaffected family members (PMID: 29663722). It has also been observed in the heterozygous state in an individual with dilated cardiomyopathy (PMID: 23349452) and in several individuals with hypertrophic cardiomyopathy, but these individuals carried additional variants in MYBPC3 and/or other cardiomyopathy-related genes (PMID: 21839045, 21415409). ClinVar contains an entry for this variant (Variation ID: 30143). Experimental studies have shown that this missense change alters MYBPC3 domain folding, but the clinical significance of this observation is uncertain (PMID: 26688216). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000619983 SCV000740231 uncertain significance Cardiovascular phenotype 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
OMIM RCV000023054 SCV000044345 pathogenic Familial hypertrophic cardiomyopathy 4 2005-10-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148675 SCV000190399 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000035516 SCV000280224 uncertain significance not specified 2015-09-08 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

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