ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.461T>C (p.Ile154Thr) (rs373946195)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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; 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 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 154 of the MYBPC3 protein (p.Ile154Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs373946195, ExAC 0.2%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (HCM) (PMID: 18403758). However, in that individual, a pathogenic allele was also identified in MYBPC3, which suggests that this c.461T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 42756). A computational algorithm designed to assess the pathogenicity of variants in MYBPC3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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 Familial hypertrophic cardiomyopathy 4 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000852656 SCV001351200 uncertain significance Cardiomyopathy 2020-11-04 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 compound heterozygous state with p.Asp605del in an individual affected with early-onset familial hypertrophic cardiomyopathy (PMID: 18403758, 18761664). 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.
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

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