chr11-47346297-C-T
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS1
The NM_000256.3(MYBPC3):c.1000G>A(p.Glu334Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.1000G>A | p.Glu334Lys | missense_variant | Exon 12 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.1000G>A | p.Glu334Lys | missense_variant | Exon 11 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.1000G>A | non_coding_transcript_exon_variant | Exon 12 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152186Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000251 AC: 62AN: 247302 AF XY: 0.000231 show subpopulations
GnomAD4 exome AF: 0.000121 AC: 177AN: 1461030Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90AN XY: 726768 show subpopulations
GnomAD4 genome 0.0000854 AC: 13AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74470 show subpopulations
ClinVar
Submissions by phenotype
not specified Uncertain:3
Variant classified as Uncertain Significance - Favor Benign. The p.Glu334Lys variant in MYBPC3 has been reported in >15 individuals with HCM (Anan 2007, Bahrudin 2008, Olivotto 2008, Gruner 2011, Zou 2013, Wang 2014, Jang 2015, Ntusi 2016, Guo 2017, Teramoto 2018, LMM data), 1 individual with DCM (Jang 2015), 1 individual with RCM (Wu 2015), and 1 individual with sudden cardiac death syndrome (Song 2017). However, no segregation data is available and at least 3 individuals with HCM carried additional variants that would be sufficient to explain their disease. Furthermore, the p.Glu334Lys variant has also been identified in 0.33% (65/19470) of East Asian chromosomes by gnomAD (gnomad.broadinstitute.org). This population frequency is significantly higher than expected for a variant causative of dominant HCM. In vitro functional studies provide some evidence that the p.Glu334Lys variant may impact protein function (Bahrudin 2011); however, these types of assays may not accurately represent biological function. Additionally, computational prediction tools and conservation analysis support that the p.Glu334Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Finally, this variant has been reported with conflicting interpretations in ClinVar (Variation ID 177902). In summary, while its frequency suggests that it is more likely to be benign, the clinical significance of the p.Glu334Lys variant remains uncertain due to the presence of conflicting data. ACMG/AMP Criteria applied: PP3; PS3_Supporting; BA1. -
Variant summary: MYBPC3 c.1000G>A (p.Glu334Lys) results in a conservative amino acid change located in the MyBP-C, tri-helix bundle domain (IPR040849) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 247302 control chromosomes, predominantly at a frequency of 0.0034 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001). c.1000G>A has been reported in the literature in multiple individuals affected with cardiomyopathies (such as sporadic hypertrophic cardiomyopathy, hypertrophic cardiomyopathy, left ventricular noncompaction cardiomyopathy, restrictive cardiomyopathy (RCM)), in sudden cardiac arrest survivors and in patients suspected of genetic disorders (example: Anan_2007, Bahrudin_2008, Guo_2017, Jang_2015, Kim_2020, Liu_2020, Ntusi_2016, Olivotto_2008, Perkins_2017, Song_2017, Teramoto_2018, Wang_2014, Wu_2015). These report however, do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic/likely pathogenic variants have been reported (MYH7 c.2123G>C, p.G708A; MYH7 c.2167C>T, p.R723C; MYH7 c.2207T>C, p.I736T; TNNI3 c.434G>A, p.R145Q; TNNI3 c.433C>T, p.R145W), providing supporting evidence for a benign role (Guo _2017, Wang_2014). In vitro over-expression studies in cell system resulted in reduced expression of the E334K mutant protein, caused Ubiquitin-proteasome system (UPS) impairment characterized by decreased level of 20S proteasome activity, increased the ratio of proapoptotic/antiapoptotic regulating protein, and increased apoptosis (Bahrudin_2008). It also enhanced Ca2+ transient amplitude resulting in cardiac electrophysiological dysfunction (Bahrudin_2011). The following publications have been ascertained in the context of this evaluation (PMID: 17560888, 18929575, 21939669, 28323875, 25856671, 32492895, 31918855, 27841901, 18533079, 29555771, 28202948, 29398688, 25132132, 26163040). ClinVar contains an entry for this variant (Variation ID: 177902). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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.Glu334Lys Based on the data reviewed below we would typically consider a variant like this to be likely disease causing. However, we are concerned about the fact that nearly all of the reported cases are Japanese and we have very few Japanese controls. Given that we are considering it a variant of uncertain significance, likely disease causing and recommending further segregation analysis and ideally waiting for more Japanese control data. The variant has been seen in at least 4 unrelated cases of cardiomyopathy. Anan et al (2007) reported the variant in one Japanese patient with HCM. Bahrudin et al (2008) observed the variant in three unrelated Japanese patients (which seem to not overlap with the report by Anan et al). Of note, given our patient's phenotype, this patient had "giant negative T-waves". These patients were reported as part of their HCM cohort, however, the authors noted that patients with this variant had systolic dysfunction (35%, 44%, 49%) and dilation (66, 50, 59). All three had left ventricular hypertrophy with IVS thicknesses of 16, 17, and 14 mm. Unfortunately only minimal clinical data is available and it is not clear if these patients first presented with classical HCM. Notably, Bahrudin et al observed the variant in 3 of 30 patients with HCM studied, which is unusually high prevalence for one variant, possibly suggesting that the variant is a common one in the Japanese population in general. They did not comment whether the patients had a shared haplotype. Gruner et al (2011) observed the variant in a patient with apical HCM from their cohort in Toronto, ancestry was not listed. In silico analysis with PolyPhen-2 predicts the variant to be benign while mutation taster predicts the variant to be disease causing. The glutamate at codon 334 is completely conserved across species, and neighboring amino acids are highly conserved. Another variant has been reported in association with disease at a nearby codon (p.Ile336Val). I could not find any other variants assocaited with disease at codon 334. Bahrudin et al (2008) reported that the myosin-binding protein was more quickly degraded by the ubiquitin-proteasome system. In total the variant has not been seen in at least ~6600 published controls and publicly available population datasets, though few of these match the ancestry of the published cases. There is no variation at codon 334 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6400 Caucasian and African American individuals (as of 1/17/2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/17/2013), this probably includes 200 individuals of various Asian ancestries, though it is hard to be sure. There is no variation at codon 334 listed in the NIEHS exome data set, which includes 24 Asian individuals (as of 27th Sept 2012). The variant was not observed in the following published control samples: Anan et al (2007) did not see the variant in 100 controls (ancestry not noted). Bahrudin et al (2008) did not see the variant in 100 controls (ancestry not noted). -
Hypertrophic cardiomyopathy 4 Uncertain:2
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions however, recessive inheritance results in a more severe early-onset phenotype (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (66 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions but very high conservation. (I) 0600 - Variant is located in the annotated tri-helix bundle domain (NCBI, PDB). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported as benign, a VUS and pathogenic in association with hypertrophic cardiomyopathy 4 (MIM#115197). It is commonly found in East Asian cohorts, and has sometimes been observed in patients with an alternative pathogenic variant in another gene that may explain their condition (ClinVar, HGMD, LOVD, PMIDs: 17560888, 31028938, 32492895). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies in transfected cells demonstrated a loss of function (PMID: 18929575). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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Hypertrophic cardiomyopathy Uncertain:1Benign:1
This missense variant replaces glutamic acid with lysine at codon 334 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). Experimental studies have shown that this variant may destabilize the protein through ubiquitin-proteasome system, modify the levels of channel proteins and induce apoptosis (PMID: 18929575, 21939669, 23740383). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 18929575, 21511876, 23283745, 23711808, 25132132, 26090888, 26163040, 32380161, 32492895, 33830315), in 5 individuals affected with dilated cardiomyopathy (PMID: 35284542), and in 1 individual affected with left ventricular non-compaction (PMID: 34853230), mostly of East Asian ancestry. This variant has also been identified in 66/278690 chromosomes (65/19470 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, 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. -
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Cardiovascular phenotype Uncertain:1Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
PP1_mod, PS3_supp, PP3, BS1 -
Cardiomyopathy Benign:2
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Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
PS3_Supporting+PS4+BS1 -
not provided Uncertain:1
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: 17560888, 27731493, 29555771, 33830315, 21939669, 23283745, 18533079, 26163040, 24380728, 23711808, 19684034, 25132132, 23740383, 21511876, 28679633, 28518168, 20045868, 24574578, 27841901, 25856671, 22455086, 33407484, 33658040, 28323875, 31918855, 31980526, 26090888, 34853230, 35130036, 29398688, 35284542, 34621001, 32380161, 32492895, 38008210, 38186735, 18929575, 37652022, 28193612, 28202948, 35534676, 37653714) -
Left ventricular noncompaction 10 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at