ClinVar Genomic variation as it relates to human health

The MYBPC3 c.2618C>A; p.Pro873His variant (rs371401403) is reported in the literature in several homozygous individuals affected with hypertrophic cardiomyopathy (HCM), as well as unaffected heterozygous relatives (Kassem 2017, Kissopoulou 2018, Nanni 2003). In addition, this variant has been reported in a proband with dilated cardiomyopathy (van Spaendonck-Zwarts 2013), and in several other individuals with HCM that carried a second missense variant of uncertain clinical significance (Maron 2012). The p.Pro873His variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (14/98008 alleles, including one homozygote) in the Genome Aggregation Database. The proline at codon 873 is highly conserved, and computational analyses (REVEL) predict that this variant is deleterious. Indeed, structural studies suggest the p.Pro873His variant leads to misfolding of the C7 domain (Nadvi 2016), although the clinical impact of this misfolding is not clear. Further, another amino acid substitution at this codon (p.Pro873Leu) has been reported in an individual with HCM, though it was not determined whether variant is disease-causing (Probst 2011). Due to limited and conflicting information, including an unclear pattern of inheritance, the clinical significance of the p.Pro873His variant is uncertain at this time. References: Kassem HS et al. A comparative study of mutation screening of sarcomeric genes (MYBPC3, MYH7, TNNT2) using single gene approach versus targeted gene panel next generation sequencing in a cohort of HCM patients in Egypt. Egypt J Med Hum Genet. 2017 Oct;18(4):381-387. Kissopoulou A et al. Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy. ESC Heart Fail. 2018 Aug;5(4):716-723. Maron BJ et al. Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors. Heart Rhythm. 2012 Jan;9(1):57-63. Nadvi NA et al. Clinically Linked Mutations in the Central Domains of Cardiac Myosin-Binding Protein C with Distinct Phenotypes Show Differential Structural Effects. Structure. 2016 Jan 5;24(1):105-115. Nanni L et al. Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. Biochem Biophys Res Commun. 2003 Sep 19;309(2):391-8. Probst S et al. Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circ Cardiovasc Genet. 2011 Aug 1;4(4):367-74. van Spaendonck-Zwarts KY et al. Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience. Eur J Heart Fail. 2013 Jun;15(6):628-36.

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.

Reported in the heterozygous state in individuals referred for cardiomyopathy genetic testing at GeneDx and in the published literature (Ingles et al., 2005; Maron et al., 2012; vanSpaendonk-Zwarts et al., 2013); however, segregation data were not provided, and multiple individuals were also found to harbor another variant in the MYBPC3 gene; Observed in the homozygous state in an individual with moderate/severe hypertrophy, left ventricular outflow tract obstruction, and non-sustained ventricular tachycardia (Nanni et al., 2003); Observed in 15/207756 (0.007%) alleles, including one homozygous individual, in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 30143; ClinVar); This variant is associated with the following publications: (PMID: 21415409, 22515980, 15115610, 25637381, 17655857, 23349452, 23299917, 21839045, 25335496, 26688216, 21551322, 18761664, 20031583, 28518168, 28679633, 12951062, 16199542, 29663722)

Variant summary: MYBPC3 c.2618C>A (p.Pro873His) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 176378 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2618C>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy and unspecified individuals from large public datasets, without strong evidence for causality (examples, Nanni_2003, Andreasen_2013, Amendola_2015, Stava_2022, vanSpaendonck_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 23299917, 35653365, 23349452, 12951062). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 873 of the MYBPC3 protein (p.Pro873His). This variant is present in population databases (rs371401403, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12951062, 29663722, 36252119; Invitae). ClinVar contains an entry for this variant (Variation ID: 30143). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 26688216). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces proline with histidine at codon 873 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has indicated that this variant may impact protein folding (PMID: 26688216), but the clinical relevance of this observation is not known. This variant has been reported in the heterozygous state in individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 21839045, 33495597; DOI:10.1016/j.ejmhg.2017.05.002) and in an individual affected with dilated cardiomyopathy (PMID: 23349452). This variant has also been reported in homozygosity in an individual affected with hypertrophic cardiomyopathy (PMID: 12951062), as well as in two related individuals from a family affected with hypertrophic cardiomyopathy (PMID: 29663722). In this family, seven unaffected heterozygous carriers were reported. This variant has been identified in 15/207756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with uncertain functional impact that has been reported in affected individuals as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces proline with histidine at codon 873 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental study has indicated that this missense may impact protein folding (PMID: 26688216), but the clinical relevance of this observation is not known. This variant has been reported in the heterozygous state in individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 21839045; Kassem 2017) and with dilated cardiomyopathy (PMID: 23349452). This variant has been reported in homozygosity in an individual affected with hypertrophic cardiomyopathy (PMID: 12951062), as well as in two related individuals from a Swedish family affected with hypertrophic cardiomyopathy (PMID: 29663722). In this Swedish family, seven unaffected heterozygous carriers were reported. This variant has also been identified in 15/207756 chromosomes (14/98008 Non-Finnish European chromosomes, including one homozygous individual) in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with uncertain functional impact that has been reported in affected individuals as well as in the general population. In a family study, multiple unaffected heterozygotes were observed in addition to two affected homozygotes. Available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The c.2618C>A (p.P873H) alteration is located in exon 26 (coding exon 26) of the MYBPC3 gene. This alteration results from a C to A substitution at nucleotide position 2618, causing the proline (P) at amino acid position 873 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (13 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (13 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Fibronectin type III domain (DECIPHER). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. The p.(Pro873Leu) variant has been reported multiple times as VUS in ClinVar and has been reported in individuals with HCM, DCM and LVNC (PMIDs: 33495597, 21551322, 27173948, 27600940). The p.(Pro873Gln) variant has been reported in one individual with HCM (PMID: 22267749). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in homozygous and compound heterozygous state in association with HCM (PMID: 12951062, 16199542, 25335496, 29663722) and in a heterozygous individual with DCM (PMID: 23349452). It has also been reported multiple times as VUS in ClinVar. (I) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate in one family with HCM, whereby individuals homozygous for the variant are affected and individuals heterozygous for the variant are unaffected (PMID: 29663722). (SP) 1206 - This variant has been shown to be paternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

The MYBPC3 Pro873His variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.00014 which is higher then expected for HCM. 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). In this proband we recently identified a third variant in CSRP3 (Arg146Cys). Both MYBPC3 variants were found to segregate to an affected first degree family member. 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, PolyPhen-2, 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".