rs397514616

Variant names:

• chr3-52452217-C-A
• rs397514616
• NM_003280.3:c.91G>T
• TNNC1 p.Ala31Ser

Your query was ambiguous. Multiple possible variants found:

• chr3-52452217-C-A
• chr3-52452217-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PM2 PP2 PP3 PP5_Moderate

The NM_003280.3(TNNC1):​c.91G>T​(p.Ala31Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004569515: Experimental studies have shown that this missense change affects TNNC1 function (PMID:22815480).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A31T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNC1 NM_003280.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91
• Publications: 26 publications found

Genes affected

TNNC1 (HGNC:11943): (troponin C1, slow skeletal and cardiac type) Troponin is a central regulatory protein of striated muscle contraction, and together with tropomyosin, is located on the actin filament. Troponin consists of 3 subunits: TnI, which is the inhibitor of actomyosin ATPase; TnT, which contains the binding site for tropomyosin; and TnC, the protein encoded by this gene. The binding of calcium to TnC abolishes the inhibitory action of TnI, thus allowing the interaction of actin with myosin, the hydrolysis of ATP, and the generation of tension. Mutations in this gene are associated with cardiomyopathy dilated type 1Z. [provided by RefSeq, Oct 2008]

TNNC1 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1Z

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004569515: Experimental studies have shown that this missense change affects TNNC1 function (PMID: 22815480).
• PM1: In a domain EF-hand 1 (size 35) in uniprot entity TNNC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003280.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.7682 (below the threshold of 3.09). Trascript score misZ: 2.6866 (below the threshold of 3.09). GenCC associations: The gene is linked to dilated cardiomyopathy 1Z, hypertrophic cardiomyopathy 13, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803
• PP5: Variant 3-52452217-C-A is Pathogenic according to our data. Variant chr3-52452217-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39832.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003280.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNC1	NM_003280.3	MANE Select	c.91G>T	p.Ala31Ser	missense	Exon 3 of 6	NP_003271.1	P63316

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNC1	ENST00000232975.8	TSL:1 MANE Select	c.91G>T	p.Ala31Ser	missense	Exon 3 of 6	ENSP00000232975.3	P63316
	TNNC1	ENST00000496590.1	TSL:2	c.-42G>T		5_prime_UTR	Exon 2 of 4	ENSP00000420596.1	C9JDI3
	TNNC1	ENST00000461086.1	TSL:2	n.-226G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000531 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 (1)
1	-	-	Hypertrophic cardiomyopathy 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	-0.84	N
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.57
Sift	Benign	0.043	D
Sift4G	Benign	0.13	T
Varity_R		0.54
gMVP		0.92
Mutation Taster		=15/85	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397514616;

hg19: chr3-52486233;