NM_003673.4(TCAP):c.110+2T>C AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 10, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002857904.3

Allele description [Variation Report for NM_003673.4(TCAP):c.110+2T>C]

NM_003673.4(TCAP):c.110+2T>C

Gene:

TCAP:titin-cap [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q12

Genomic location:

Preferred name:

NM_003673.4(TCAP):c.110+2T>C

HGVS:

NC_000017.11:g.39665471T>C
NG_008892.1:g.5126T>C
NG_042278.1:g.2491T>C
NM_003673.4:c.110+2T>CMANE SELECT
LRG_210:g.5126T>C
NC_000017.10:g.37821724T>C

Molecular consequence:

NM_003673.4:c.110+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hypertrophic cardiomyopathy 25 (CMH25)
Synonyms:: CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 25
Identifiers:: MONDO: MONDO:0011843; MedGen: C4225408; OMIM: 607487

Name:: Primary familial hypertrophic cardiomyopathy (HCM)
Synonyms:: Hereditary ventricular hypertrophy; Idiopathic hypertrophic subaortic stenosis
Identifiers:: MONDO: MONDO:0024573; MeSH: D024741; MedGen: C0949658; OMIM: PS192600

Recent activity

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RBBP5[gene] (26)
ClinVar
Leuconostoc mesenteroides strain P3A4, whole genome shotgun sequencing project
Leuconostoc mesenteroides strain P3A4, whole genome shotgun sequencing project
gi|2675949434|gb|JAZHLD000000000.1| D010000000

Nucleotide
PREDICTED: Homo sapiens RB binding protein 5, histone lysine methyltransferase c...
PREDICTED: Homo sapiens RB binding protein 5, histone lysine methyltransferase complex subunit (RBBP5), transcript variant X2, mRNA
gi|2462512112|ref|XM_054338011.1|

Nucleotide
PREDICTED: Varanus komodoensis calpain 3 (CAPN3), transcript variant X3, mRNA
PREDICTED: Varanus komodoensis calpain 3 (CAPN3), transcript variant X3, mRNA
gi|2118000527|ref|XM_044436847.1|

Nucleotide
natural resistance-associated macrophage protein 1 isoform X1 [Caretta caretta]
natural resistance-associated macrophage protein 1 isoform X1 [Caretta caretta]
gi|2263205364|ref|XP_048724673.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003229619	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 10, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003229619

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 10, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003229619.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TCAP protein in which other variant(s) (p.Cys57*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with TCAP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the TCAP gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine