rs74315380

Variant names:

• chr1-201364366-G-A
• rs74315380
• NM_001276345.2:c.421C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-201364366-G-A
• chr1-201364366-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.421C>T​(p.Arg141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.06
• Publications: 74 publications found

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

TNNT2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

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

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

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000286600 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 25 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201364366-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 389145.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 1-201364366-G-A is Pathogenic according to our data. Variant chr1-201364366-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.421C>T	p.Arg141Trp	missense	Exon 11 of 17	NP_001263274.1
	TNNT2	NM_000364.4		c.421C>T	p.Arg141Trp	missense	Exon 11 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.421C>T	p.Arg141Trp	missense	Exon 11 of 16	NP_001393652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.421C>T	p.Arg141Trp	missense	Exon 11 of 17	ENSP00000499593.1
	TNNT2	ENST00000367322.6	TSL:1	c.388C>T	p.Arg130Trp	missense	Exon 10 of 15	ENSP00000356291.2
	TNNT2	ENST00000367320.6	TSL:1	c.301C>T	p.Arg101Trp	missense	Exon 10 of 15	ENSP00000356289.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460434 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726570

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111936

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Dilated cardiomyopathy 1D (3)
2	-	-	Cardiovascular phenotype (2)
1	-	-	Cardiomyopathy, familial restrictive, 3 (1)
1	-	-	Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 (1)
1	-	-	Hypertrophic cardiomyopathy 2 (1)
1	-	-	not provided (1)
1	-	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.44		Loss of methylation at R141 (P = 0.2583)
MVP		0.98
MPC		1.4
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.74
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs74315380; hg19: chr1-201333494;