11-47342697-C-T
Variant summary
Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_000256.3(MYBPC3):c.1505G>A(p.Arg502Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,898 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502G) has been classified as Likely pathogenic.
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: Pathogenic. The variant received 14 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | c.1505G>A | p.Arg502Gln | missense_variant | Exon 17 of 35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.1505G>A | p.Arg502Gln | missense_variant | Exon 17 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.1505G>A | p.Arg502Gln | missense_variant | Exon 16 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.1505G>A | non_coding_transcript_exon_variant | Exon 17 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 33 show subpopulations
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461692Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727132 show subpopulations
Age Distribution
GnomAD4 genome 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74368 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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.Arg502Gln Based on the data reviewed below, we consider this variant very likely disease causing. This variant has been seen in at least 9 unrelated cases of HCM with moderately strong segregation data in two different families. Niimura et al (1998) first reported the variant in two families with HCM. The variant segregated with disease in 4 members of one family and 5 members of the other, with the furthest degree of relationship between affecteds with the variant in each family being 2nd degree. Cardim et al (2005) observed the variant in a Portugese patient with HCM. Rudzinski et al (2008) observed the variant in one Polish HCM patient. Girolami et al (2006) observed the variant in two unrelated patients with HCM (likely the same two families in Olivotto et al 2008). Morita et al (2008) observed p.Arg502Gln in a child with HCM. A German group observed the variant in one patient with HCM (Ehlermann et al 2008). This may be the same case reported in a methods paper by Zeller et al (2006). Rodriguez-Garcia et al (2010) observed the variant in two unrelated Spanish families with HCM and in one of those families there were two affected individuals with the variant. The arginine at codon 502 is highly conserved. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Another variant (p.Arg502Trp) at the same codon, which we consider very likely disease causing, was recently reported as the most common HCM-causing variant with a frequency of 2.4% in HCM patients (Saltzman et al 2010). Variants in nearby codons have also been reported in association with HCM (p.Arg495Gln, p.Lys505del, p.Gly507Arg). In total the variant has not been seen in ~418 published controls: 100 (Niimura et al 1998), 118 (Rudzinski et al 2008), 200 (Rodriguez-Garcia et al 2010). p.Arg502Gln is not listed in the NHLBI Exome Sequencing Project dataset, however, p.Arg502Trp was observed in 1 of 3472 Caucasians and 0 of 1826 Caucasians in that dataset (as of 1/16/2012). Individual phenotypes from that dataset are not available. Several different cohorts from studies on common complex cardiovascular disease were pooled to create that sample. There is no variant at codon 502 listed in dbSNP or 1000 genomes (as of 1/16/2012). -
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Not observed at significant frequency in large population cohorts (gnomAD); 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: 20298698, 15115610, 20378854, 32952175, 34097875, 34060810, 16715312, 31918855, 27532257, 18803133, 25342278, 22386539, 27600940, 26507537, 26183555, 25892673, 18957093, 22857948, 24093860, 24510615, 20433692, 22112859, 18403758, 16566405, 16858239, 18533079, 17224687, 22267749, 30645170, 29687901, 20738943, 29907873, 28166811, 21310275, 28193612, 31006259, 31447099, 30847666, 33658040, 9562578, 31589614, 12106841, 33407484, 34400558, 35208637, 36243179, 36264615, 36252119, 36136372, 35653365, 12707239) -
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Hypertrophic cardiomyopathy 4 Pathogenic:7
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PM5+PM2_Supporting+PP3+PS4+PP1_Strong -
This sequence change in MYBPC3 is predicted to replace arginine with glutamine at codon 502, p.(Arg502Gln). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the Ig-like C2-type 3 domain in a region (amino acids 485-502), that is defined as a mutational hotspot (PMID: 30696458). There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.007% (5/74,922 alleles) in the African/African American population. The prevalence of the variant in individuals with hypertrophic cardiomyopathy (HCM) is significantly increased compared with the prevalence in the population (30 in 11,582 case genotypes vs 5 in 589,947 control genotypes giving an odds ratio of 306.4, 95%CI=118.9-789.9; PMID: 20433692, 25611685, 28771489, 32481709, 37652022; gnomAD v4.1). The variant has been reported to segregate with HCM in multiple families (PMID: 9562578, 20433692). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.645). Another missense variant with a larger physicochemical difference (c.1504C>T p.Arg502Trp) in the same codon has been classified as pathogenic for HCM (ClinVar ID: 42540). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PP1_Strong, PP3, PS4. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cardiomyopathy. (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset hypertrophic and dilated cardiomyopathies, however recessive inheritance is associated with a severe early onset hypertrophic cardiomyopathy (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 an arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (13 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin I-set domain (NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (ClinVar, PMID: 31308319, 31771441). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042541, PMID:9562578, PS1_S). A different missense change at the same codon has been reported to be associated with MYBPC3 related disorder (ClinVar ID: VCV000042540, PMID:12707239,26090888, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.645, 3CNET: 0.973, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Hypertrophic cardiomyopathy Pathogenic:5
The p.Arg502Gln variant in MYBPC3 has been identified in at least 15 individuals with HCM and segregated with disease in 8 affected relatives from 3 families (N iimura 1998, Olivotto 2008, Rodriguez-Garcia 2010, Otsuka 2012, LMM data). It ha s also been reported by other clinical laboratories in ClinVar (Variation ID 425 41) and was absent from large population studies. Another missense variant in t he same codon (p.Arg502Trp) is one of the most common pathogenic MYBPC3 variants associated with HCM, supporting that this codon is critical for MYBPC3 protein function. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon presence in multiple affecte d individuals, segregation studies, absence from the general population, and occ urrence in a critical codon. ACMG/AMP criteria applied (Richards 2015): PS4, PP1 _Strong, PM5, PM2. -
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This missense variant replaces arginine with glutamine at codon 502 in the Ig-like domain C3 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 over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 16566405, 18403758, 18533079, 20433692, 22112859, 22267749, 22857948, 27600940, 28193612, 31308319). It has been shown that this variant segregates with hypertrophic cardiomyopathy in multiple affected individuals across multiple unrelated families (PMID: 20433692, 22112859). This variant has also been reported in one individual affected with left ventricular noncompaction cardiomyopathy who also carried a different pathogenic truncation variant in the same gene (PMID: 31918855). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg502Trp, is considered to be disease-causing (ClinVar variation ID: 42540), suggesting that arginine at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic. -
This heterozygous missense variant in the MYBPC3 gene was identified in a baby with neonatal hypertrophic cardiomyopathy. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 502 of the MYBPC3 protein (p.Arg502Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9562578, 16566405, 18403758, 18533079, 20433692, 22386539). ClinVar contains an entry for this variant (Variation ID: 42541). 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. This variant disrupts the p.Arg502 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 20378854, 22267749, 23396983). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Cardiomyopathy Pathogenic:2
This missense variant replaces arginine with glutamine at codon 502 in the Ig-like domain C3 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 over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 16566405, 18403758, 18533079, 20433692, 22112859, 22267749, 22857948, 27600940, 28193612, 31308319). It has been shown that this variant segregates with hypertrophic cardiomyopathy in multiple affected individuals across multiple unrelated families (PMID: 20433692, 22112859). This variant has also been reported in one individual affected with left ventricular noncompaction cardiomyopathy who also carried a different pathogenic truncation variant in the same gene (PMID: 31918855). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg502Trp, is considered to be disease-causing (ClinVar variation ID: 42540), suggesting that arginine at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic. -
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Cardiovascular phenotype Pathogenic:2
The p.R502Q pathogenic mutation (also known as c.1505G>A) is located in coding exon 17 of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1505. The arginine at codon 502 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM) including several families with strong evidence of segregation with disease (Nimura etal. N Engl J Med. 1998;338:1248-1257; Cardmin N etal. Rev Port Cardiol. 2005;24:1463-147; Rudzinski T etal. Kardiol Pol. 2008;66:821-825; Otsuka H et al. Circ. J. 2012;76(2):453-61; Maurizi N et al. JAMA Cardiol. 2018;3(6):520-525). This alteration has also been reported in an individual with HCM who also had evidence of left ventricular noncompaction (Faria R etal. Rev Port Cardiol. 2012;31:317-319). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
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Left ventricular noncompaction 10 Pathogenic:1
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Primary familial hypertrophic cardiomyopathy Pathogenic:1
Variant summary: MYBPC3 c.1505G>A (p.Arg502Gln) results in a conservative amino acid change located in the immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250000 control chromosomes (gnomAD and publications). c.1505G>A has been reported in the literature in many individuals affected with Hypertrophic Cardiomyopathy (HCM), including in several unrelated families where it primarily segregated with the disease phenotype (e.g. Niimura_1998, Girolami_2006, Miller_2007, Morita_2008, Rodriguez-Garcia_2010, Otsuka_2012, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. A variant affecting the same codon, p.Arg502Trp, has also been reported to be associated with HCM, suggesting that the Arg502 residue is likely important for MYBPC3 protein function. Fourteen submitters have provided assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
MYBPC3-related disorder Pathogenic:1
The MYBPC3 c.1505G>A variant is predicted to result in the amino acid substitution p.Arg502Gln. This variant has been reported to segregate with hypertrophic cardiomyopathy in multiple unrelated families (See for example – Niimura et al. 1998. PubMed ID: 9562578; Jordan et al. 2011. PubMed ID: 21310275; Table S1A/B in Walsh et al. 2017. PubMed ID: 27532257) and has been interpreted as pathogenic by multiple clinical labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/42541/). Additionally, different amino acid substitutions (p.Arg502Gly, p.Arg502Trp, p.Arg502Leu) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). We classify the c.1505G>A (p.Arg502Gln) variant as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at