rs193922385
Variant summary
Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3
The NM_000256.3(MYBPC3):c.529C>T(p.Arg177Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000964 in 1,607,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R177P) has been classified as Likely benign.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 4Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- left ventricular noncompaction 10Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- atrial fibrillationInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 1 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.529C>T | p.Arg177Cys | missense_variant | Exon 5 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.529C>T | p.Arg177Cys | missense_variant | Exon 5 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.529C>T | non_coding_transcript_exon_variant | Exon 5 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.0000988 AC: 15AN: 151796Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000685 AC: 16AN: 233730 AF XY: 0.0000549 show subpopulations
GnomAD4 exome AF: 0.0000962 AC: 140AN: 1455282Hom.: 0 Cov.: 31 AF XY: 0.0000954 AC XY: 69AN XY: 723300 show subpopulations
Age Distribution
GnomAD4 genome 0.0000988 AC: 15AN: 151796Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74120 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:6
Identified in patients with cardiomyopathy in published literature (Miller et al., 2013; Pugh et al., 2014; Walsh et al., 2017; van Waning et al., 2018; Aljeaid et al., 2019; Verdonschot et al., 2020; Burstein et al., 2021; van der Meulen et al., 2022 ); of note, several patients harbored pathogenic or likely pathogenic variants in other cardiomyopathy-related genes; Identified in a family with a history of DCM and congenital heart abnormalities; however, the proband from this family and other affected relatives also harbored a missense variant in the VCL gene, and the most severely affected individuals harbored both the MYBPC3 and VCL variants (Wells et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 27532257, 30762279, 25637381, 23299917, 22555271, 28518168, 33782553, 32880476, 32746448, 36178741, 34097875, 24503780, 24062880, 29447731, 23054336) -
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Found on postmortem testing of a 17-year-old with a negative autopsy and a history of 2 seizures in one day and then a sudden death a few months later. A 148-gene Arrhythmia and Cardiomyopathy Comprehensive Panel was done by the Invitae laboratory. This included Sudden Death in Epilepsy genes. Results included 3 variants: -p.Thr368Ile (c.1103C>T) in the DSC2 gene -p.Ala647Val (c.1940C>T) in the LAMA4 gene -p.Arg177Cys (c.529C>T) in the MYBPC3 gene p.Arg177Cys (c.529C>T) in exon 5 of the MYBPC3 gene (NM_000256.3) Chromosome location 11:47371450 G / A Based on the information reviewed below, we classify Arg177Cys as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. A different variant at this same location, Arg177His, has been classified in ClinVar as Benign by multiple labs. This variant has previously been reported in at least 3 unrelated families with cardiomyopathy, however in a family with hypertrophic cardiomyopathy there was also a pathogenic truncating variant in MYBPC3, suggesting that the Arg177Cys variant was not the primary cause of disease. LMM in ClinVar reports seeing Arg177Cys in two families with DCM; in one of these families a VUS in the VCL gene was also present. There were no affected relatives who harbored only the Arg177Cys, but there was one relative with DCM who had only the VUS in VCL, suggesting that Arg177Cys failed to segregate with disease (it was present in 3 out of 4 affected family members tested). However, the most severely affected family members each had both the MYBPC3 and VCL variants, so it is possible that they both play a role (Wells et al., 2011). This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine capable of forming disulfide bridges. Arginine at this location is poorly conserved across ~100 vertebrate species for which we have data. It is most frequently changed to another positively-charged amino acid, but Valine and Glutamine are other alternatives. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. LMM’s computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant was reported in 17 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 4 East Asian ancestry individuals (for the highest allele frequency: 0.02%), 3 African, 3 Latino, and 7 non-Finnish European ancestry individuals. Overall MAF 0.0065%. Of note: Whiffin et al (2017) proposed that variants with frequency greater than 0.004% are unlikely to be pathogenic in HCM. A different variant at this same location, Arg177His, is present in 305 individuals in gnomAD, with a MAF of 1.3% among individuals with African ancestry and 0.05% among Latinos. 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. The curators made an effort to exclude individuals with severe pediatric diseases. -
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Hypertrophic cardiomyopathy 4 Uncertain:3
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Cardiomyopathy Uncertain:2
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This missense variant replaces arginine with cysteine at codon 177 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 22555271, 30762279). One of these individuals carried a pathogenic truncation variant in the same gene (PMID: 22555271). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 24062880, 24503780, 27532257, 32746448, 32880476, 36178741). One of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 36178741). This variant has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 29447731). This variant has been identified in 17/265018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Hypertrophic cardiomyopathy Uncertain:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 177 of the MYBPC3 protein (p.Arg177Cys). This variant is present in population databases (rs193922385, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated or hypertrophic cardiomyopathy (PMID: 22555271, 24062880, 27532257, 30762279, 32746448, 32880476, 33782553, 36178741). ClinVar contains an entry for this variant (Variation ID: 36613). 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. 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 arginine with cysteine at codon 177 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 22555271, 30762279). One of these individuals carried a pathogenic truncating variant in the same gene (PMID: 22555271). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 24062880, 24503780, 27532257, 32746448, 32880476, 36178741). One of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 36178741). This variant has also been reported in an individual affected with non-compaction cardiomyopathy (PMID: 29447731). This variant has been identified in 17/265018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Cardiovascular phenotype Uncertain:2
The c.529C>T (p.R177C) alteration is located in exon 5 (coding exon 5) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 529, causing the arginine (R) at amino acid position 177 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
PM2 -
not specified Uncertain:1Benign:1
Variant summary: MYBPC3 c.529C>T (p.Arg177Cys) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 233730 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (6.8e-05 vs 0.001), allowing no conclusion about variant significance. However, another variant at the same residue (p.Arg177His) is present at allele frequency of 1.3% in African subpopulation in gnomAD, strongly suggesting it to be a likely benign polymorphism, thus the residue p.Arg177 may not be critical for protein function. c.529C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy (example: Kindel_2012, Wells_2011, Waning_2018, Alijeaid_2019, Verdonschot_2020, Bursetein_2021, Suay-Corredara_2021). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported in our internal data or publications (MYPBC3 c.3811C>T, p.R1271*; MYPBC3 c.1235_1236delTT, p.Ile411_Phe412insTer; RAF1 c.769T>C, p.Ser257Pro) (Kindel_2012, Alijeaid_2019), providing supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Variant classified as Uncertain Significance - Favor Benign. The Arg177Cys varia nt in MYBPC3 has been reported in 1 adult with HCM who carried another pathogeni c variant in the MYBPC3 gene(Cardiogenomics) and was identified by our laborator y in 2 individuals with DCM (Wells 2011, LMM unpublished data), one of whom carr ied a second variant of unknown significance in VCL. In 1 family with DCM this v ariant was found to segregate with disease in 2/3 affected family members. The A rg177Cys variant has been identified in 1/8398 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs19 3922385). Arginine (Arg) at position 177 not well conserved in mammals or evolut ionarily distant species and the change to cysteine (Cys) was predicted to be be nign using a computational tool clinically validated by our laboratory. This too l's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In addition, another change at the same position (Arg177His) is present in 1% of the general population (42/4088 African American chromosomes, NHLBI Exome Seque ncing Project), suggesting that changes at this position may not affect the prot ein. In summary, while these data argue against a disease-causing role when pres ent in isolation, a modifying effect cannot be ruled out and additional studies are needed to fully establish the clinical significance of this variant. -
Left ventricular noncompaction 10 Uncertain:1
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Primary familial hypertrophic cardiomyopathy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at