11-47346336-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_000256.3(MYBPC3):c.961G>A(p.Val321Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,608,044 control chromosomes in the GnomAD database, including 1 homozygotes. 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
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.961G>A | p.Val321Met | missense_variant | Exon 12 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.961G>A | p.Val321Met | missense_variant | Exon 11 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.961G>A | non_coding_transcript_exon_variant | Exon 12 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.000243 AC: 37AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000344 AC: 82AN: 238522Hom.: 0 AF XY: 0.000371 AC XY: 48AN XY: 129512
GnomAD4 exome AF: 0.000455 AC: 663AN: 1455690Hom.: 1 Cov.: 32 AF XY: 0.000422 AC XY: 305AN XY: 723560
GnomAD4 genome 0.000243 AC: 37AN: 152354Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15AN XY: 74496
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:6
Previously reported in association with DCM and HCM, however, some reported individuals also harbored variants in other cardiomyopathy-related genes (Waldmuller et al., 2011; Maron et al., 2012; Lopes et al., 2013; Miller et al., 2013; Lopes et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23396983, 23299917, 21839045, 24721642, 31737537, 31274156, 21750094, 25637381, 22958901, 26633542, 23054336, 27418595, 27896284, 27153395, 28807990, 28518168, 27930701, 29914921, 30324321, 25351510) -
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not specified Uncertain:4
Variant classified as Uncertain Significance - Favor Benign. The p.Val321Met var iant in MYBPC3 has been identified in 2 individuals with DCM, 6 individuals with HCM, 1 individual with LVNC and 1 individual with TOF (Hoedemaekers 2011, Waldm uller 2011, Maron 2012, Lopes 2013, Miller 2013, LaHaye 2016, LMM unpublished da ta). It has also been identified in 0.1% (36/45024) of European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2 00119454). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, while the clinical significance of the p.Val321Met variant is uncertain, its frequency and the broad spectrum of a ssociated diseases suggest that it is more likely to be benign. -
Variant summary: MYBPC3 c.961G>A (p.Val321Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 238522 control chromosomes, predominantly at a frequency of 0.00057 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (0.00034 vs 0.001), allowing no conclusion about variant significance. c.961G>A has been reported in the literature in individuals affected with Cardiomyopathy, without strong evidence for causality (Andreasen_2013, Maron_2012, McGurk_2023, Millar_2013, Stava_2022, Waldmuller_2011). These report(s) do not provide unequivocal conclusions about association of the variant with 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: 23299917, 21839045, 37652022, 23054336, 35653365, 21750094). ClinVar contains an entry for this variant (Variation ID: 161310). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
The MYBPC3 c.961G>A; p.Val321Met variant (rs200119454) is reported in the literature in multiple individuals affected with dilated and hypertrophic cardiomyopathy (Waldmuller 2011, lopes 2013 and Lopes 2015). However, multiple papers have suggested that this variant may be too frequent to cause cardiomyopathy without additional factors (Andreasen 2013, Maxwell 2016, Nouhravesh 2016 and Whiffin 2017). This variant is found in the general population with an overall allele frequency of 0.03 % (89/269,910 alleles) in the Genome Aggregation Database. The valine at codon 321 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to conflicting information, the clinical significance of the p.Val321Met variant is uncertain at this time. -
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. p.Val321Met (c.961G>A) in the MYBPC3 gene. Data on the variant is reviewed below. Given that many of the patients with this variant have an additional variant and also that p.Val321Met is present in a general population sample, we consider it a variant of uncertain significance. In total, the variant has been seen in 6 cases of cardiomyopathy (not including the patient) with no segregation data available. Notably, in 3 of 6 cases the patients carried at least one other rare sarcomere variant (and in 2 of 6 cases data is not available on the presence or absence of additional variants). Waldmuller et al (2011) observed the variant in one individual with DCM out of 888 individuals with HCM or DCM studied (note that this allele frequency is consistent with the allele frequency observed in the NHBLI dataset). They sequenced MYBPC3 and MYH7 in this cohort and did note that some patients had multiple variants however they don't specify which variants were seen in the presence of another variant. The variant was also observed in one of 327 Dutch individuals with HCM and was classified as a variant of uncertain significance in that study (Hoedemakers et al in http://repub.eur.nl/res/pub/22183/110114_Michels,%20Michelle.pdf). They only report on analysis of MYBPC3. It has also been seen by GeneDx in two other patients with HCM. One of them also had another variant in MYBPC3, which GeneDx described as a "published mutation" (the did not share what the variant was). McKenna's group observed the variant in one out of 223 HCM probands in their UK cohort (Lopes et al 2013). That patient also carried p.Lys351Glu in MYH7 and p.Val176Met in TNNI3 (we have not reviewed either of these variants). Maron et al (2012) reported the variant in a patient with HCM who also carried p.Val411IIe in MYH7 (we have not reviewed that variant). The reported cohort of 330 patients was drawn from the Tufts, Minneapolis heart institute, and Sydney HCM centers. The variant is not currently listed in ClinVar (as of November 20th, 2014). This is a conservative amino acid substitution with a nonpolar Valine replaced with a nonpolar Methionine. The amino acid change is located in a highly conserved domain of the protein and residue 321 is conserved across mammals, however it is an Alanine in Elegans. In silico analysis with Polyphen 2 predicts the variant to be probably damaging. Additional variants in nearby codons (p.Ser311Leu, p.Arg326Gln) have been reported in association with cardiomyopathy. In total the variant is present in 5 of 6408 individuals from publicly available databases. The variant was reported in the NHLBI Exome Sequencing Project data set in 4 of 4250 Caucasian individuals and 1 of 2158African-American individuals (as of December 28, 2011). The phenotype of these individuals is not publicly available, however the cohort has been screened to exclude individuals with evidence of Mendelian cardiac disease. GeneDx reports that the variant was absent in 353 presumably healthy individuals of mixed ancestry. The variant is listed in dbSNP (rs200119454); the ESP data is the only data referenced in the dbSNP entry. I also checked the Exome Aggregation Consortium dataset, a newly released dataset of exomes on ~64,000 individuals from a variety of research studies. This overlaps with the ESP data reviewed above. We are still reviewing this dataset and assessing how to apply it clinically. The datasets includes 37 heterozygotes with this variant, out of a total of 40,521 individuals of varied ancestries. The highest frequency is 36 heterozygotes in 22,820 individuals of European decent. Phenotype is available on one of those patients, published by th -
Hypertrophic cardiomyopathy 4 Uncertain:3
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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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Cardiomyopathy Uncertain:1Benign:2
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Hypertrophic cardiomyopathy Uncertain:1Benign:2
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Primary dilated cardiomyopathy Uncertain:2
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Primary familial hypertrophic cardiomyopathy Uncertain:1
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MYBPC3-related disorder Uncertain:1
The MYBPC3 c.961G>A variant is predicted to result in the amino acid substitution p.Val321Met. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Lopes et al. 2013. PubMed ID: 23396983, Table S1; Dewar et al. 2017. PubMed ID: 28807990, Table S2). However, this variant has a sub-population frequency of up to 0.11% in the gnomAD population database, which is more frequent than expected for a pathogenic variant in MYBPC3. Also, this variant was found along with an alternate molecular basis for disease and authors classified it as likely benign (Whiffin et al. 2017. PubMed ID: 28518168, Supplementary Table S1). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Cardiovascular phenotype Benign: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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at