rs730881115

chr1-201364335-CG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001276345.2(TNNT2):c.451del(p.Arg151GlyfsTer41) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000837 in 1,613,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R151R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9
• Conservation: PhyloP100: 5.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.451del	p.Arg151GlyfsTer41	frameshift_variant	11/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.451del	p.Arg151GlyfsTer41	frameshift_variant	11/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 250100 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000842 AC: 123 AN: 1460954 Hom.: 0 Cov.: 31 AF XY: 0.0000826 AC XY: 60 AN XY: 726796

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2018	The c.421delC variant of uncertain significance in the TNNT2 gene has reported in multiple individuals with DCM (Millat et al., 2011; Hirtle-Lewis et al., 2013; Broch et al., 2015; Meng et al., 2017) and also has been reported in one individual with HCM (van Velzen et al., 2016). Millat et al. (2011) identified this variant in an individual with DCM and observed segregation with disease in three affected family members. The c.421delC variant is observed in 14/126,390 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This variant causes a shift in reading frame starting at codon arginine 141, changing it to a glycine, and creating a premature stop codon at position 41 of the new reading frame, denoted p.Arg141GlyfsX41. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, the vast majority of variants in TNNT2 are missense changes, indicating haploinsufficiency of TNNT2 may not be sufficient to cause cardiomyopathy. Some truncating variants have been reported in association with familial cardiomyopathy (Stenson et al., 2014), however these changes are commonly present at the last and penultimate exons of the TNNT2 gene.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TNNT2: PS4:Moderate, PP1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2023	PP1 -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 09, 2021	- -

Dilated cardiomyopathy 1D Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	May 25, 2016	This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. To date, it is not known whether loss-of-function is a disease mechanism for the TNNT2 gene. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 25, 2019	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP5. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Sep 26, 2023

PVS1_Mod;PS4_Supp;PM2;PP1 -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 18, 2023

This variant deletes 1 nucleotide in exon 10 of the TNNT2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 21846512, 26468400), including four affected individuals from a family (PMID: 21846512). This variant has also been identified in 14/281472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation and splice variants in the TNNT2 gene is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2023

The c.421delC variant, located in coding exon 9 of the TNNT2 gene, results from a deletion of one nucleotide at nucleotide position 421, causing a translational frameshift with a predicted alternate stop codon (p.R141Gfs*41). This alteration has been reported in a case of familial dilated cardiomyopathy and was reported to segregate with disease in the family (Millat G et al. Eur J Med Genet 2011 Aug;54:e570-5). This alteration has also been reported in an infant with dilated cardiomyopathy, congenital heart disease and respiratory distress and has been seen in a hypertrophic cardiomyopathy (HCM) cohort (Meng L et al. JAMA Pediatr, 2017 12;171:e173438; van Velzen HG et al. Circ Genom Precis Med, 2018 04;11:e001896). This alteration has also been seen in an exome cohort, but cardiovascular history was not provided (Retterer K et al. Genet. Med., 2016 Jul;18:696-704). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TNNT2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change creates a premature translational stop signal (p.Arg141Glyfs*41) in the TNNT2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNT2 cause disease. This variant is present in population databases (rs730881115, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 21846512, 26468400, 28973083). ClinVar contains an entry for this variant (Variation ID: 181635). 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

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: rs730881115; hg19: chr1-201333463;