rs397516863

Variant names:

• chr17-39666077-C-A
• rs397516863
• NM_003673.4:c.472C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-39666077-C-A
• chr17-39666077-C-G
• chr17-39666077-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_003673.4(TCAP):​c.472C>A​(p.Arg158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TCAP NM_003673.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-39666077-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 17-39666077-C-A is Pathogenic according to our data. Variant chr17-39666077-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44711.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCAP	NM_003673.4	c.472C>A	p.Arg158Ser	missense_variant	Exon 2 of 2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.472C>A	p.Arg158Ser	missense_variant	Exon 2 of 2	1	NM_003673.4	ENSP00000312624.2
TCAP	ENST00000578283.1	c.400C>A	p.Arg134Ser	missense_variant	Exon 3 of 3	5		ENSP00000462787.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449934 Hom.: 0 Cov.: 34 AF XY: 0.00000277 AC XY: 2 AN XY: 721694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Sep 30, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features of autosomal dominant dilated cardiomyopathy. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Polyphen and MutationTaster yielded discordant predictions regarding whether this amino acid change is damaging to the protein. -

Jul 25, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in several individuals with DCM or referred for DCM genetic testing (PMID: 26084686, 27532257, Cuesta-Llavona et al., 2022; 24503780); at least one individual harbored an additional variant that was thought to contribute to the phenotype (PMID: 24503780); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 27532257, Cuesta-Llavona_2022_Cardiogenetics, 16490376, 26084686) -

Feb 24, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:1

Jan 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TCAP c.472C>A (p.Arg158Ser) results in a non-conservative amino acid change located in the Telethonin protein (IPR015667) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241542 control chromosomes. c.472C>A has been reported in the literature in individuals affected with Cardiomyopathy (Pugh_2014, Akinrinade_2015, Walsh_2017, Invitae) and segregates with disease. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported.The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 26084686, 27532257). ClinVar contains an entry for this variant (Variation ID: 44711). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hypertrophic cardiomyopathy Pathogenic:1

Dec 14, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 158 of the TCAP protein (p.Arg158Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy (PMID: 26084686, 27532257; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44711). 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. This variant disrupts the p.Arg158 amino acid residue in TCAP. Other variant(s) that disrupt this residue have been observed in individuals with TCAP-related conditions (PMID: 24037902; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Sep 21, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg158Ser variant in TCAP has not been reported in the literature. It has be en identified by our laboratory in 2 individuals with DCM, one of whom carried a second, likely pathogenic variant. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.52		Gain of phosphorylation at R158 (P = 0.0174);.;
MVP		0.98
MPC		1.0
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.85
gMVP		0.55

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

Other links and lift over

dbSNP: rs397516863; hg19: chr17-37822330;