Submissions for variant NM_000256.3(MYBPC3):c.461T>C (p.Ile154Thr)

gnomAD frequency: 0.00019  dbSNP: rs373946195

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035631	SCV000059282	uncertain significance	not specified	2015-10-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ile154Thr var iant in MYBPC3 has been identified by our laboratory as heterozygous in 1 Caucas ian infant with DCM and as homozygous in 1 child with HCM (Morita 2008, LMM unpu blished data), who also carries another homozygous variant (p.Asp605del) in this gene. The p.Ile154Thr variant has also been identified in 0.2% (5/2428) of Afri can chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs373946195). Isoleucine (Ile) at position 154 is not conserved in evolutionarily distant species and multiple fish species carry a threonine a t this position. Additionally, the change to threonine (Thr) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011 ). In summary, while the clinical significance of the p.Ile154Thr variant is unc ertain, these data suggest that it is more likely to be benign.
GeneDx	RCV000035631	SCV000208216	uncertain significance	not specified	2016-01-05	criteria provided, single submitter	clinical testing	The I154T variant of uncertain significance in the MYBPC3 gene has been reported previously in one child diagnosed with HCM who also harbored another variant in the MYBPC3 gene, and reported I154T was absent in at least 360 ethnically-matched control alleles (Morita et al., 2008). Nevertheless, the 1000 Genomes Project reports was observed in 5/1322 alleles (0.4%) from individuals of African ancestry, indicating it may be a rare benign variant in this population. Additionally, another clinical laboratory classifies I154T as a variant of uncertain significance (Landrum et al., 2014). The I154T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, T154 is present in several species. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae	RCV000532512	SCV000623610	uncertain significance	Hypertrophic cardiomyopathy	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 154 of the MYBPC3 protein (p.Ile154Thr). This variant is present in population databases (rs373946195, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 18403758, 32746448). ClinVar contains an entry for this variant (Variation ID: 42756). 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 tolerated. 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852656	SCV000995362	likely benign	Cardiomyopathy	2018-11-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000988555	SCV001138320	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000852656	SCV001351200	uncertain significance	Cardiomyopathy	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 154 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 an individual affected with hypertrophic cardiomyopathy (PMID: 32841044) and in an individual affected with dilated cardiomyopathy (PMID: 32746448). This variant has been reported in compound heterozygous state with p.Asp605del in an individual affected with early-onset familial hypertrophic cardiomyopathy (PMID: 18403758, 18761664); this individual also carried an additional pathogenic variant in the MYBPC3 gene. This variant has also been identified in 20/206608 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	RCV000035631	SCV001448477	uncertain significance	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.461T>C (p.Ile154Thr) results in a non-conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 175200 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Cardiomyopathy (7.4e-05 vs 0.001), allowing no conclusion about variant significance. c.461T>C has been reported in the literature in one individual affected with idiopathic cardiac hypertrophy. This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=6, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV003162304	SCV003911249	likely benign	Cardiovascular phenotype	2023-03-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CSER _CC_NCGL, University of Washington	RCV000148686	SCV000190413	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786367	SCV000925170	uncertain significance	not provided	2016-03-01	no assertion criteria provided	provider interpretation
Clinical Genetics, Academic Medical Center	RCV000786367	SCV001925444	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000786367	SCV001969707	uncertain significance	not provided		no assertion criteria provided	clinical testing