3-52451799-C-T

Position:

• chr3-52451799-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The ENST00000232975.8(TNNC1):​c.262G>A​(p.Asp88Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D88Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNC1 ENST00000232975.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Troponin C, slow skeletal and cardiac muscles (size 160) in uniprot entity TNNC1_HUMAN there are 27 pathogenic changes around while only 0 benign (100%) in ENST00000232975.8
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52451799-C-T is Pathogenic according to our data. Variant chr3-52451799-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181563.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNC1	NM_003280.3	c.262G>A	p.Asp88Asn	missense_variant	4/6	ENST00000232975.8	NP_003271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNC1	ENST00000232975.8	c.262G>A	p.Asp88Asn	missense_variant	4/6	1	NM_003280.3	ENSP00000232975	P1
TNNC1	ENST00000496590.1	c.130G>A	p.Asp44Asn	missense_variant	3/4	2		ENSP00000420596
TNNC1	ENST00000461086.1	n.193G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2013

This variant is denoted p.Asp88Asn (GAC>AAC): c.262 G>A in exon 4 of the TNNC1 gene (NM_003280.2). The Asp88Asn variant in the TNNC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp88Asn results in a semi-conservative amino acid substitution of one negatively charged Aspartic acid with a neutral, polar Asparagine at a position that is conserved across species. In silico algorithms are not consistent in their predictions but at least two concur Asp88Asn is damaging to the protein structure/function. Mutations in nearby residues (Asp75Tyr, Cys84Tyr, Met103Ile) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Asp88Asn variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Asp88Asn is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The pathogenic role for this variant would be further supported if it co-segregates with a cardiomyopathy phenotype in this family. The variant is found in DCM panel(s). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2019

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. 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. This variant has not been reported in the literature in individuals with TNNC1-related disease. ClinVar contains an entry for this variant (Variation ID: 181563). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 88 of the TNNC1 protein (p.Asp88Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.96	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.38	N;N
REVEL	Uncertain	0.57
Sift	Benign	0.066	T;T
Sift4G	Benign	0.21	T;.
Polyphen		0.32	B;.
Vest4		0.60
MutPred		0.27		Loss of ubiquitination at K86 (P = 0.0396);.;
MVP		0.85
MPC		0.55
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.47
gMVP		0.84

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: rs730881058; hg19: chr3-52485815; COSMIC: COSV51767003; COSMIC: COSV51767003;