NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln) AND multiple conditions

Clinical significance:Pathogenic (Last evaluated: Aug 20, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000627784.5

Allele description [Variation Report for NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)]

NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)

Gene:
TNNT2:troponin T2, cardiac type [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q32.1
Genomic location:
Preferred name:
NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)
Other names:
p.R92Q:CGG>CAG
HGVS:
  • NC_000001.11:g.201365297C>T
  • NG_007556.1:g.17381G>A
  • NM_000364.4:c.305G>A
  • NM_001001430.3:c.275G>A
  • NM_001001431.3:c.275G>A
  • NM_001001432.3:c.260G>A
  • NM_001276345.2:c.305G>AMANE SELECT
  • NM_001276346.2:c.291+313G>A
  • NM_001276347.2:c.275G>A
  • NP_000355.2:p.Arg102Gln
  • NP_001001430.1:p.Arg92Gln
  • NP_001001431.1:p.Arg92Gln
  • NP_001001432.1:p.Arg87Gln
  • NP_001263274.1:p.Arg102Gln
  • NP_001263276.1:p.Arg92Gln
  • LRG_431t1:c.305G>A
  • LRG_431:g.17381G>A
  • LRG_431p1:p.Arg102Gln
  • NC_000001.10:g.201334425C>T
  • NM_001001430.1:c.275G>A
  • NM_001001430.2:c.275G>A
  • c.275G>A
Protein change:
R102Q; ARG92GLN
Links:
OMIM: 191045.0002; dbSNP: rs121964856
NCBI 1000 Genomes Browser:
rs121964856
Molecular consequence:
  • NM_001276346.2:c.291+313G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000364.4:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001430.3:c.275G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001431.3:c.275G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001432.3:c.260G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276345.2:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276347.2:c.275G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial hypertrophic cardiomyopathy 2 (CMH2)
Synonyms:
Hypertrophic cardiomyopathy 2; TNNT2-Related Familial Hypertrophic Cardiomyopathy
Identifiers:
MONDO: MONDO:0007266; MedGen: C1861864; OMIM: 115195
Name:
Left ventricular noncompaction 6 (CMD1D)
Synonyms:
Dilated cardiomyopathy 1D
Identifiers:
MONDO: MONDO:0011095; MedGen: C1832243; Orphanet: 154; Orphanet: 54260; OMIM: 601494
Name:
Familial restrictive cardiomyopathy 3 (RCM3)
Identifiers:
MONDO: MONDO:0012900; MedGen: C2676271; Orphanet: 75249; OMIM: 612422

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000285648Invitaecriteria provided, single submitter
Pathogenic
(Aug 20, 2020)
germlineclinical testing

PubMed (19)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.

Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE.

Cell. 1994 Jun 3;77(5):701-12.

PubMed [citation]
PMID:
8205619

Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.

Watkins H, McKenna WJ, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG, et al.

N Engl J Med. 1995 Apr 20;332(16):1058-64.

PubMed [citation]
PMID:
7898523
See all PubMed Citations (19)

Details of each submission

From Invitae, SCV000285648.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (19)

Description

This sequence change replaces arginine with glutamine at codon 92 of the TNNT2 protein (p.Arg92Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypertrophic cardiomyopathy (HCM) in many families (PMID: 8205619, 7898523). In addition, it has been described in several individuals affected with HCM (PMID: 8951566, 23233322, 25524337), in one individual with left ventricular non-compaction (LVNC) (PMID: 24691700), in one individual with an atypical pattern of myocardial scarring (PMID: 19087273) and in one individual with inducible malignant ventricular tachyarrhythmia (PMID: 19487599). This variant has also been suggested to have arisen de novo in an individual affected with HCM (PMID: 18403758). ClinVar contains an entry for this variant (Variation ID: 12409). Different missense substitutions at this codon (p.Arg92Trp, p.Arg92Leu) are reported to be deleterious (PMID: 9060892, 16326803, 22144547). Functional studies have demonstrated that several substitutions between codons 91 and 110, including p.Arg92, impair tropomyosin-dependent functions of troponin T (PMID: 11606294) indicating that this missense change is located within a functionally conserved domain of the TNNT2 protein. This indicates that the arginine residue is important for TNNT2 protein function. Experimental studies have shown that this missense change results in an increase in Ca2+ sensitivity of force development (PMID: 10085122, 12186860). Although transgenic mice did not develop HCM, they showed increased cardiac contractility and histopathological findings consistent with HCM (PMID: 9788962, 10449439, 11158969). In summary, this rare missense variant has been found in multiple affected individuals, segregates with the disease and has been found to have an impact on protein function. For these reasons, it has been classified as Pathogenic.

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

Last Updated: Nov 27, 2021

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