Submissions for variant NM_000256.3(MYBPC3):c.1112C>T (p.Pro371Leu)

gnomAD frequency: 0.00001  dbSNP: rs397515887

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158332	SCV000208267	uncertain significance	not provided	2020-02-27	criteria provided, single submitter	clinical testing	Identified in patients with cardiomyopathy in the published literature (Walsh et al., 2017; Ito et al., 2017; Li et al., 2018); At the protein level, in silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27532257, 28679633, 30371277, 31397097)
Color Diagnostics, LLC DBA Color Health	RCV001180561	SCV001345519	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 371 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32830170, 33487615). This variant has been identified in 6/245804 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203567	SCV001374740	uncertain significance	Hypertrophic cardiomyopathy	2025-01-15	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 371 of the MYBPC3 protein (p.Pro371Leu). This variant is present in population databases (rs397515887, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or left ventricular noncompaction (PMID: 27532257, 31397097, 32830170, 33487615). ClinVar contains an entry for this variant (Variation ID: 181060). 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. This variant disrupts the p.Pro371 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 35208637), which suggests that this may be a clinically significant amino acid residue. 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	RCV001180561	SCV004239333	uncertain significance	Cardiomyopathy	2023-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001203567	SCV004834672	uncertain significance	Hypertrophic cardiomyopathy	2024-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 371 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32830170, 33487615). It has also been reported in an individual affected with left ventricular noncompaction who also carried a pathogenic truncation variant in the DMD gene (PMID: 31397097). This variant has been identified in 6/245804 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	RCV004639151	SCV005144241	uncertain significance	Cardiovascular phenotype	2024-04-15	criteria provided, single submitter	clinical testing	The p.P371L variant (also known as c.1112C>T), located in coding exon 13 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1112. The proline at codon 371 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Nakashima Y et al. Circ J, 2020 Sep;84:1846-1853). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.