Submissions for variant NM_000256.3(MYBPC3):c.1243A>C (p.Ile415Leu)

gnomAD frequency: 0.00003  dbSNP: rs1269517446

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756370	SCV000884162	uncertain significance	not specified	2019-03-14	criteria provided, single submitter	clinical testing	The p.Ile415Leu variant has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) Browser with an overall population frequency of 0.006 percent (identified on 2 out of 30,950 chromosomes). The isoleucine at position 415 is moderately conserved from human to zebrafish (Alamut v.2.9.0), and computational analyses of the effects of the p.Ile415Leu variant on protein structure and function indicates no deleterious effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ile415Leu variant with certainty.
Invitae	RCV000824650	SCV000965557	uncertain significance	Hypertrophic cardiomyopathy	2022-12-20	criteria provided, single submitter	clinical testing	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 618225). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 415 of the MYBPC3 protein (p.Ile415Leu).
Color Diagnostics, LLC DBA Color Health	RCV001178146	SCV001342518	uncertain significance	Cardiomyopathy	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 415 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 2/31388 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000756370	SCV002511452	uncertain significance	not specified	2022-04-08	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1243A>C (p.Ile415Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 243266 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1243A>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002298755	SCV002588112	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002386315	SCV002673109	uncertain significance	Cardiovascular phenotype	2021-09-02	criteria provided, single submitter	clinical testing	The p.I415L variant (also known as c.1243A>C), located in coding exon 15 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 1243. The isoleucine at codon 415 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV001250999	SCV001426399	likely pathogenic	Left ventricular noncompaction 10		flagged submission	research