ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3323A>C (p.Lys1108Thr) (rs397516015)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035578 SCV000059228 uncertain significance not specified 2012-04-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Lys1108Thr variant (MYBPC3) has not been reported in the literature nor previously identifi ed in >2000 Caucasian probands tested by our laboratory. Lysine (Lys) at postion 1108 is highly conserved through distantly related species and computational an alyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Lys1108Thr variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. Although this data supports that the Lys1108Thr variant may be pathogenic, additional studies are needed to fully assess its clinical significance.
GeneDx RCV000035578 SCV000208162 uncertain significance not specified 2017-09-12 criteria provided, single submitter clinical testing The K1108T variant of uncertain significance in the MYBPC3 gene has been previously reported in association with HCM (Bick et al., 2012; Alder et al., 2016). Bick et al. (2012) first reported K1108T in a 76 year-old individual from the Framingham Heart Study Offspring cohort without cardiomyopathy. Alder et al. (2016) identified K1108T in their cohort of patients with HCM, although further clinical details describing this patient's specific phenotype were not provided. In addition, K1108T has been identified independently of additional cardiogenetic variants in two other individuals referred for HCM genetic testing at GeneDx. Thus far, no informative segregation data are available for these published cases or those observed at GeneDx. The K1108T variant is observed in 15/116048 (0.01%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The K1108T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is likely damaging to the protein structure/function.
Invitae RCV000476105 SCV000546495 uncertain significance Hypertrophic cardiomyopathy 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 1108 of the MYBPC3 protein (p.Lys1108Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs397516015, ExAC 0.008%). This variant has been reported in an individual with arrhythmia, as well as in one individual without cardiomyopathy from the Framingham Offspring Study participants (PMID: 26743238, 22958901). ClinVar contains an entry for this variant (Variation ID: 42704). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000620941 SCV000740220 uncertain significance Cardiovascular phenotype 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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