NM_003280.3(TNNC1):c.23C>T (p.Ala8Val) AND Hypertrophic cardiomyopathy 13

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000013256.38

Allele description [Variation Report for NM_003280.3(TNNC1):c.23C>T (p.Ala8Val)]

NM_003280.3(TNNC1):c.23C>T (p.Ala8Val)

Gene:

TNNC1:troponin C1, slow skeletal and cardiac type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.1

Genomic location:

Preferred name:

NM_003280.3(TNNC1):c.23C>T (p.Ala8Val)

Other names:

p.A8V:GCG>GTG

HGVS:

NC_000003.12:g.52453993G>A
NG_008963.1:g.5049C>T
NG_033112.1:g.3486G>A
NM_003280.3:c.23C>TMANE SELECT
NP_003271.1:p.Ala8Val
LRG_378t1:c.23C>T
LRG_378:g.5049C>T
NC_000003.11:g.52488009G>A
NM_003280.2:c.23C>T
P63316:p.Ala8Val
c.23C>T

Protein change:

A8V; ALA8VAL

Links:

UniProtKB: P63316#VAR_063070; OMIM: 191040.0003; dbSNP: rs267607125

NCBI 1000 Genomes Browser:

rs267607125

Molecular consequence:

NM_003280.3:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy 13
Synonyms:: Familial hypertrophic cardiomyopathy 13; TNNC1-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0013195; MedGen: C2750472; OMIM: 613243

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033503	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2008)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV003835274	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841812	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18572189, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000033503

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2008)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV003835274

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 28, 2022)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003841812

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

unknown

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.

Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ.

J Mol Cell Cardiol. 2008 Aug;45(2):281-8. doi: 10.1016/j.yjmcc.2008.05.003. Epub 2008 May 11.

PubMed [citation]

PMID:: 18572189
PMCID:: PMC2627482

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000033503.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 37-year-old Caucasian man who was diagnosed at 33 years of age with hypertrophic cardiomyopathy (CMH13; 613243) after presenting with dyspnea, Landstrom et al. (2008) identified heterozygosity for a c.23C-T transition in exon 1 of the TNNC1 gene, resulting in an ala8-to-val (A8V) substitution in the N-helix of the N-terminal domain. Functional studies using mutant porcine cardiac skinned fibers showed significantly increased force development and force recovery compared to wildtype. The mutation was not found in 400 Caucasian or 100 African American controls with normal screening ECGs and echocardiograms.

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

From Baylor Genetics, SCV003835274.1

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

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

From 3billion, SCV003841812.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18572189). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012443). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Apr 20, 2025

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