ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1805C>T (p.Thr602Ile)

gnomAD frequency: 0.00001  dbSNP: rs730880551
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158117 SCV000208052 uncertain significance not provided 2023-11-09 criteria provided, single submitter clinical testing Identified in patients with HCM or LVNC in published literature (PMID: 34540771, 24793961, 31568572, 31333075); Identified in a fetal sample from a consanguineous couple with CNS anomalies including agenesis of corpus collosum, hygroma colli, interhemispheric cyst, abnormal skull shape, and hypertelorism (PMID: 34611884); this variant was considered an incidental finding in this case.; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 31568572, 31333075, 36264615, 24793961, 34611884, 34540771)
Klaassen Lab, Charite University Medicine Berlin RCV000853169 SCV000995883 likely pathogenic Left ventricular noncompaction cardiomyopathy criteria provided, single submitter research
AiLife Diagnostics, AiLife Diagnostics RCV000158117 SCV002501864 uncertain significance not provided 2022-02-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV002408712 SCV002714918 uncertain significance Cardiovascular phenotype 2023-07-11 criteria provided, single submitter clinical testing The p.T602I variant (also known as c.1805C>T), located in coding exon 19 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1805. The threonine at codon 602 is replaced by isoleucine, an amino acid with similar properties. This variant was reported in a hypertrophic cardiomyopathy (HCM) cohort; however clinical details were limited (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37). This variant was also reported in an individual with left ventricular non-compaction (LVNC), who had an additional MYH7 variant detected; her unaffected father was also found to have this p.T602I variant, whereas her affected mother was heterozygous for the MYH7 variant (Al-Wakeel-Marquard N et al. J Am Heart Assoc, 2019 Aug;8:e012531; Kühnisch J et al. Clin. Genet., 2019 Sep;[Epub ahead of print]). This amino acid position is well 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.
Invitae RCV002516378 SCV003270425 uncertain significance Hypertrophic cardiomyopathy 2022-08-21 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 602 of the MYBPC3 protein (p.Thr602Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and left ventricular noncompaction cardiomyopathy (PMID: 24793961, 31568572). ClinVar contains an entry for this variant (Variation ID: 180950). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65". The isoleucine 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.