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NM_003283.6(TNNT1):c.538G>T (p.Glu180Ter) AND Nemaline myopathy 5

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Mar 3, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description [Variation Report for NM_003283.6(TNNT1):c.538G>T (p.Glu180Ter)]

NM_003283.6(TNNT1):c.538G>T (p.Glu180Ter)

TNNT1:troponin T1, slow skeletal type [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_003283.6(TNNT1):c.538G>T (p.Glu180Ter)
  • NC_000019.10:g.55137176C>A
  • NG_011829.2:g.17063G>T
  • NM_001126132.3:c.538G>T
  • NM_001126133.3:c.505G>T
  • NM_001291774.2:c.505G>T
  • NM_003283.6:c.538G>TMANE SELECT
  • NP_001119604.1:p.Glu180Ter
  • NP_001119605.1:p.Glu169Ter
  • NP_001278703.1:p.Glu169Ter
  • NP_003274.3:p.Glu180Ter
  • LRG_679t1:c.538G>T
  • LRG_679:g.17063G>T
  • LRG_679p1:p.Glu180Ter
  • NC_000019.9:g.55648544C>A
  • NM_003283.4:c.538G>T
  • NM_003283.5:c.538G>T
  • p.0
  • r.538g>u
Protein change:
E169*; GLU180TER
Leiden Muscular Dystrophy (TNNT1): TNNT1_00001; OMIM: 191041.0001; dbSNP: rs80358249
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001126132.3:c.538G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001126133.3:c.505G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001291774.2:c.505G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_003283.6:c.538G>T - nonsense - [Sequence Ontology: SO:0001587]
Functional consequence:
functional variant [Sequence Ontology: SO:0001536]


Nemaline myopathy 5 (NEM5A)
Nemaline Myopathy, Amish Type; Nemaline myopathy, caused by mutation in the troponin t1 gene; Nemaline myopathy 5, Amish type; See all synonyms [MedGen]
MONDO: MONDO:0011539; MedGen: C1854380; Orphanet: 98902; OMIM: 605355

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
no assertion criteria provided
(Apr 8, 2005)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

no classification provided
not providedunknownliterature only

PubMed (4)
[See all records that cite these PMIDs]

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
(Mar 3, 2023)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownnot providednot providednot providednot providednot providednot providedliterature only




North KN, Ryan MM.

2002 Jun 19 [updated 2015 Jun 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

Nemaline myopathy caused byTNNT1 mutations in a Dutch pedigree.

van der Pol WL, Leijenaar JF, Spliet WG, Lavrijsen SW, Jansen NJ, Braun KP, Mulder M, Timmers-Raaijmakers B, Ratsma K, Dooijes D, van Haelst MM.

Mol Genet Genomic Med. 2014 Mar;2(2):134-7. doi: 10.1002/mgg3.52. Epub 2013 Dec 12.

PubMed [citation]
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000033500.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)


In affected individuals with autosomal recessive severe infantile nemaline myopathy-5A (NEM5A; 605355), also known as Amish nemaline myopathy, Johnston et al. (2000) identified a homozygous c.579G-T transversion in exon 11 of the TNNT1 gene, resulting in a stop codon at amino acid 180 (E180X) and loss of 83 C-terminal residues. Johnston et al. (2000) had treated or obtained clinical information on 71 infants and young children from 33 nuclear Amish families with this form of nemaline myopathy. In the first months of life, affected infants had tremors with hypotonia and mild contractures of the shoulders and hips. Progressive worsening of the proximal contractures, weakness, and a pectus carinatum deformity developed before the children died of respiratory insufficiency, usually in the second year.

Variant Function

Jin et al. (2003) found complete loss of the TNNT1 protein in patients with the E180X mutation. The truncated protein results in elimination of the C-terminal T2 domain that interacts with troponin C (TNNC1; 191040), I (TNNI2; 191043), and tropomyosin (TPM1; 191010), but was predicted to retain a central tropomyosin-binding site that participates in the anchoring of troponin complex to the thin actin filament. If residual truncated protein was produced, this could potentially result in a dominant-negative effect. The significant muscle atrophy observed in the disorder was consistent with the slow Tnt isoform being involved in muscle development and growth.

In a patient with Amish nemaline myopathy due to the E180X mutation, Wang et al. (2005) detected residual mutant TNNT1 mRNA in muscle tissue but no corresponding translated mutant TNNT1 protein. In vitro functional expression studies in nonmuscle cells showed that E180X-mutant protein could be produced but was not detectable when expressed in muscle cells in vitro. The findings suggested rapid degradation of E180X-mutant protein in muscle cells, rather than a loss of nonsense mRNA to explain the absence of a dominant effect. Wang et al. (2005) postulated that inefficient incorporation of mutant TNNT1 into myofilaments results in its degradation by the muscle cell as a protective mechanism.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000041024.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Invitae, SCV000763599.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)


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.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024