3-52453993-G-C

Position:

• chr3-52453993-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_003280.3(TNNC1):​c.23C>G​(p.Ala8Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNC1 NM_003280.3 missense, splice_region
• Scores: Splicing: ADA: 0.9947
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.11

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Troponin C, slow skeletal and cardiac muscles (size 160) in uniprot entity TNNC1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_003280.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-52453993-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNC1	NM_003280.3	c.23C>G	p.Ala8Gly	missense_variant, splice_region_variant	1/6	ENST00000232975.8	NP_003271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNC1	ENST00000232975.8	c.23C>G	p.Ala8Gly	missense_variant, splice_region_variant	1/6	1	NM_003280.3	ENSP00000232975.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1Z;C2750472:Hypertrophic cardiomyopathy 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 19, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 8 of the TNNC1 protein (p.Ala8Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant has not been reported in the literature in individuals with TNNC1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Ala8 amino acid residue in TNNC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27574918, 18572189, 19439414, 21056975, 20459070). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.59	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.11	T
Polyphen		0.21	B
Vest4		0.68
MutPred		0.52		Gain of catalytic residue at A7 (P = 0.0607);
MVP		0.88
MPC		2.0
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.79
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52488009;