rs80358249

Positions:

• chr19-55137176-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_003283.6(TNNT1):​c.538G>T​(p.Glu180*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 151,572 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.00015 (0 hom., cov: 30)
• Consequence: TNNT1 NM_003283.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 7.22

Genes affected

TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-55137176-C-A is Pathogenic according to our data. Variant chr19-55137176-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12440.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-55137176-C-A is described in Lovd as [Pathogenic]. Variant chr19-55137176-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT1	NM_003283.6	c.538G>T	p.Glu180*	stop_gained	11/14	ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6	c.538G>T	p.Glu180*	stop_gained	11/14	1	NM_003283.6	ENSP00000467176.1

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151572 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0253

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251174 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135824

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.000152 AC: 23 AN: 151572 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74000

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000227

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 5 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 08, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 03, 2023	This sequence change creates a premature translational stop signal (p.Glu180*) in the TNNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNNT1 are known to be pathogenic (PMID: 10952871, 24689076, 25430424). This variant is present in population databases (rs80358249, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 10952871). It is commonly reported in individuals of Amish ancestry (PMID: 10952871). ClinVar contains an entry for this variant (Variation ID: 12440). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TNNT1 function (PMID: 12732643, 15665378, 27429059). For these reasons, this variant has been classified as Pathogenic. -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (TNNT1)

Mar 18, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.84
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80358249; hg19: chr19-55648544;