rs730880610
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5BP4_Strong
The NM_000256.3(MYBPC3):c.305C>T(p.Pro102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,501,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P102T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.305C>T | p.Pro102Leu | missense_variant | 3/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.305C>T | p.Pro102Leu | missense_variant | 3/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.305C>T | p.Pro102Leu | missense_variant | 3/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.305C>T | p.Pro102Leu | missense_variant, NMD_transcript_variant | 3/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000187 AC: 2AN: 107026Hom.: 0 AF XY: 0.0000169 AC XY: 1AN XY: 59050
GnomAD4 exome AF: 0.00000889 AC: 12AN: 1349414Hom.: 0 Cov.: 31 AF XY: 0.0000120 AC XY: 8AN XY: 665766
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74348
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 16, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 probands, no segs - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2016 | The P102L variant of uncertain significance has previously been reported in two unrelated Egyptian individuals with HCM and was absent from 200 ethnicity-matched control alleles (Kassem et al., 2013). This variant was reported as 'de novo' in both of these individuals; however, specific family history information or data on parental testing was not provided (Kaseem et al., 2013). The P102L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and Leucine is the wild type amino acid at this position in at least two species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Data from control individuals was not available to assess whether P102L may be a common benign variant in the general population. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 15, 2023 | This missense variant replaces proline with leucine at codon 102 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 23233322; doi:10.25560/95088) as well as in several healthy individuals (doi:10.25560/95088). This variant has been identified in 2/107026 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 27, 2017 | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 102 of the MYBPC3 protein (p.Pro102Leu). This variant is present in population databases (rs730880610, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23233322; Invitae). ClinVar contains an entry for this variant (Variation ID: 181030). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces proline with leucine at codon 102 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 at least two individuals affected with hypertrophic cardiomyopathy (PMID: 23233322; doi:10.25560/95088) as well as in several healthy individuals (doi:10.25560/95088). This variant has been identified in 2/107026 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
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 12, 2024 | The p.P102L variant (also known as c.305C>T), located in coding exon 3 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 305. The proline at codon 102 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at