ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.305C>T (p.Pro102Leu)

gnomAD frequency: 0.00003  dbSNP: rs730880610
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158274 SCV000208209 uncertain significance not specified 2016-04-19 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000158274 SCV000539824 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing 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
Invitae RCV000524970 SCV000623581 uncertain significance Hypertrophic cardiomyopathy 2024-01-29 criteria provided, single submitter clinical testing 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769365 SCV000900753 uncertain significance Cardiomyopathy 2017-01-27 criteria provided, single submitter clinical testing
Mendelics RCV000988556 SCV001138321 uncertain significance Hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000769365 SCV001352614 uncertain significance Cardiomyopathy 2023-11-15 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV002444655 SCV002753656 uncertain significance Cardiovascular phenotype 2018-05-21 criteria provided, single submitter clinical testing 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 variant was detected in two individuals from a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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