NM_003673.4:c.337C>T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_003673.4(TCAP):c.337C>T(p.Leu113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,612,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_003673.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152248Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000144 AC: 36AN: 249588Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135412
GnomAD4 exome AF: 0.000175 AC: 255AN: 1460724Hom.: 0 Cov.: 30 AF XY: 0.000182 AC XY: 132AN XY: 726702
GnomAD4 genome AF: 0.000125 AC: 19AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Reported in association with HCM although clinical and segregation data were not provided (Lopes et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 25351510, 16490376) -
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Cardiovascular phenotype Uncertain:2
The p.L113F variant (also known as c.337C>T), located in coding exon 2 of the TCAP gene, results from a C to T substitution at nucleotide position 337. The leucine at codon 113 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is well conserved in available vertebrate species; however, phenylalanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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not specified Uncertain:1
The p.Leu113Phe variant in TCAP has been identified by our laboratory in 1 indiv idual with HCM, but has also been identified in 11/64214 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s372312912). This variant has also been reported in ClinVar (Variation ID: 17903 2). Computational prediction tools and conservation analysis suggest that the p .Leu113Phe variant may not impact the protein, though this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Leu113Phe variant is uncertain. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
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Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 113 of the TCAP protein (p.Leu113Phe). This variant is present in population databases (rs372312912, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TCAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 179032). 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 disruptive. 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. -
Autosomal recessive limb-girdle muscular dystrophy type 2G;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at