rs786205076

chr17-39665466-AGG-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003673.4(TCAP):c.110_110+1del variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E36E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCAP NM_003673.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.09

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 22 pathogenic variants in the truncated region.
• PP5: Variant 17-39665466-AGG-A is Pathogenic according to our data. Variant chr17-39665466-AGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 5526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-39665466-AGG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCAP	NM_003673.4	c.110_110+1del		frameshift_variant, splice_region_variant	1/2	ENST00000309889.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCAP	ENST00000309889.3	c.110_110+1del		frameshift_variant, splice_region_variant	1/2	1	NM_003673.4	P1
TCAP	ENST00000578283.1	c.110_110+1del		frameshift_variant, splice_region_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2022

The c.110_110+1delGG pathogenic mutation results from a deletion of 2 nucleotides between positions 110 and 110+1 and involves the canonical splice donor site after coding exon 1 of the TCAP gene. This alteration has been reported in a family with limb girdle muscular dystrophy and cardiac involvement, who was compound heterozygous for an additional alteration in TCAP (Moreira ES et al. Nat Genet. 2000 Feb;24(2):163-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2021

This sequence change creates a premature translational stop signal (p.Gly37Leufs*5) in the TCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 131 amino acid(s) of the TCAP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy type 2G (PMID: 10655062). It has also been observed to segregate with disease in related individuals. This variant is also known as c.110_110+1del. ClinVar contains an entry for this variant (Variation ID: 5526). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the TCAP protein in which other variant(s) (p.Gln53*) have been determined to be pathogenic (PMID: 10655062, 23479141, 25298746). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive limb-girdle muscular dystrophy type 2G;C4225408:Hypertrophic cardiomyopathy 25 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 17, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2G Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

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: rs786205076; hg19: chr17-37821719;