11-47346303-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000256.3(MYBPC3):c.994G>A(p.Glu332Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,613,086 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 Uncertain significance (★★).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.994G>A | p.Glu332Lys | missense_variant | Exon 12 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.994G>A | p.Glu332Lys | missense_variant | Exon 11 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.994G>A | non_coding_transcript_exon_variant | Exon 12 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000324 AC: 8AN: 246592Hom.: 0 AF XY: 0.0000299 AC XY: 4AN XY: 133988
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1460752Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 726580
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74486
ClinVar
Submissions by phenotype
not provided Uncertain:2
The E332K variant in the MYBPC3 gene has been reported as a variant of uncertain significance in association with DCM (Pugh et al., 2014). Pugh et al. (2014) identified the E332K variant in two unrelated individuals with a clinical and family history of DCM, one of whom also harbored a likely pathogenic variant in the MYH7 gene. The E332K variant has been also reported as a pathogenic variant, but clinical information was not provided (Zimmerman R et al., 2010). The E332K variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E332K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -
We identified this variant in a patient with DCM. Testing was performed at Invitae. SCICD Classification: variant of uncertain significance based on relatively high frequency in the general population, weak case data (and different phenotypes), and variant type. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): 1 DCM, 1 HCM Pugh et al 2014 - redundant with LMM Clinvar data. Zimmerman 2010 - technical paper on sequencing chip; redundant with LMM ClinVar data. Walsh et al 2016 - reports an additional patient with this variant with HCM tested at Oxford laboratory. Classified as VUS. The supplement also includes the previously reported two LMM DCM cases. Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive." Conservation data: Glu is highly conserved. Nearby pathogenic variants at this codon or neighboring codons: There are other nearby pathogenic variants, but they are nonsense variants, not missense. Population data: Highest MAF in Latino population: 0.02096%. The variant was reported online in 8 of 121912 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 7 of 16700 individuals of Latino descent (MAF=0.02%). 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. -
Hypertrophic cardiomyopathy Uncertain:2
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. 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. ClinVar contains an entry for this variant (Variation ID: 42815). This missense change has been observed in individuals with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397516086, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 332 of the MYBPC3 protein (p.Glu332Lys). -
This missense variant replaces glutamic acid with lysine at codon 332 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). It has also been reported in individuals affected with dilated cardiomyopathy; one of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 24503780, 27532257). This variant has been identified in 8/246592 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. -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Glu332Lys variant in MYBPC3 has been reported in 2 individuals with DCM and 1 individual with HCM, one of whom carried an additional pathogenic variant in MYBPC3 (Walsh 2017, LMM data). It did not segregate with disease in 1 affected family member with DCM (LMM data). It has also been identified in 0.02% (7/34248) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #42815). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting, BS4. -
Cardiomyopathy Uncertain:1
This missense variant replaces glutamic acid with lysine at codon 332 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). It has also been reported in individuals affected with dilated cardiomyopathy; one of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 24503780, 27532257). This variant has been identified in 8/246592 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 4 Uncertain:1
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Cardiovascular phenotype Uncertain:1
The c.994G>A (p.E332K) alteration is located in exon 12 (coding exon 12) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 994, causing the glutamic acid (E) at amino acid position 332 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at