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

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

TCAP
NM_003673.4 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 0.877
Variant links:
Genes affected
TCAP (HGNC:11610): (titin-cap) Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.23918754).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCAPNM_003673.4 linkc.337C>T p.Leu113Phe missense_variant Exon 2 of 2 ENST00000309889.3 NP_003664.1 O15273A2TDC0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCAPENST00000309889.3 linkc.337C>T p.Leu113Phe missense_variant Exon 2 of 2 1 NM_003673.4 ENSP00000312624.2 O15273
TCAPENST00000578283.1 linkc.265C>T p.Leu89Phe missense_variant Exon 3 of 3 5 ENSP00000462787.1 J3KT40

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152248
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000144
AC:
36
AN:
249588
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135412
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000258
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000175
AC:
255
AN:
1460724
Hom.:
0
Cov.:
30
AF XY:
0.000182
AC XY:
132
AN XY:
726702
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000216
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152248
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000230
Hom.:
0
Bravo
AF:
0.000140
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000273
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:4
Oct 11, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 26, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 18, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Nov 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:2
Mar 16, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Institute of Human Genetics, Medical University Innsbruck
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Jan 11, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jul 27, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
24
DANN
Benign
0.85
DEOGEN2
Uncertain
0.65
D;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.78
T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.24
T;T
MetaSVM
Uncertain
0.36
D
MutationAssessor
Uncertain
2.1
M;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.8
N;.
REVEL
Uncertain
0.36
Sift
Benign
0.046
D;.
Sift4G
Benign
0.16
T;T
Polyphen
0.99
D;.
Vest4
0.099
MVP
0.97
MPC
0.96
ClinPred
0.15
T
GERP RS
4.5
Varity_R
0.20
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372312912; hg19: chr17-37822195; API