rs397515981
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000256.3(MYBPC3):c.2654C>T(p.Thr885Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,564,538 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
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2654C>T | p.Thr885Met | missense_variant | Exon 26 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.2654C>T | p.Thr885Met | missense_variant | Exon 25 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.*159C>T | non_coding_transcript_exon_variant | Exon 26 of 27 | 5 | ENSP00000444259.1 | ||||
MYBPC3 | ENST00000544791.1 | n.*159C>T | 3_prime_UTR_variant | Exon 26 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 30
GnomAD4 exome AF: 0.0000269 AC: 38AN: 1412348Hom.: 0 Cov.: 33 AF XY: 0.0000257 AC XY: 18AN XY: 699122
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:3
This missense variant replaces threonine with methionine at codon 885 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 21302287). This variant has also been identified in 6/228884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in two individuals with HCM (Roncarti 2011, Millat 2010). Gnomad: 0.013% (2 alleles). Clinvar: VUS (Invitae). -
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 885 of the MYBPC3 protein (p.Thr885Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20624503, 21302287). ClinVar contains an entry for this variant (Variation ID: 42649). 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. -
Cardiomyopathy Uncertain:1
This missense variant replaces threonine with methionine at codon 885 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 21302287, 27532257, 32481709). This variant has been identified in 6/228884 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;C3715165:Left ventricular noncompaction 10 Uncertain:1
- -
not provided Uncertain:1
Identified in patients with hypertrophic cardiomyopathy (HCM) in the published literature (Millat et al., 2010; Roncarati et al., 2011; Walsh et al., 2017); 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: 27532257, 21302287, 20624503) -
Cardiovascular phenotype Uncertain:1
The c.2654C>T (p.T885M) alteration is located in exon 26 (coding exon 26) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2654, causing the threonine (T) at amino acid position 885 to be replaced by a methionine (M). 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