U.S. flag

An official website of the United States government

NM_000363.5(TNNI3):c.146dup (p.Lys50fs) AND Hypertrophic cardiomyopathy

Germline classification:
Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:
May 4, 2023
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003770141.5

Allele description [Variation Report for NM_000363.5(TNNI3):c.146dup (p.Lys50fs)]

NM_000363.5(TNNI3):c.146dup (p.Lys50fs)

Gene:
TNNI3:troponin I3, cardiac type [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
19q13.42
Genomic location:
Preferred name:
NM_000363.5(TNNI3):c.146dup (p.Lys50fs)
HGVS:
  • NC_000019.10:g.55156607dup
  • NG_007866.2:g.6126dup
  • NM_000363.5:c.146dupMANE SELECT
  • NP_000354.4:p.Lys50fs
  • LRG_432t1:c.146dup
  • LRG_432:g.6126dup
  • NC_000019.9:g.55667974_55667975insA
  • NC_000019.9:g.55667975dup
  • NC_000019.9:g.55667975dup
  • NM_000363.4:c.146dup
  • NM_000363.4:c.146dupT
Protein change:
K50fs
Links:
dbSNP: rs1162696593
NCBI 1000 Genomes Browser:
rs1162696593
Molecular consequence:
  • NM_000363.5:c.146dup - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

Condition(s)

Name:
Hypertrophic cardiomyopathy
Synonyms:
HYPERTROPHIC MYOCARDIOPATHY
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004669680Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Mar 11, 2023)
germlineclinical testing

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

SCV004821888All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(May 4, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Molecular Diagnosis of Primary Cardiomyopathy in 231 Unrelated Pediatric Cases by Panel-Based Next-Generation Sequencing: A Major Focus on Five Carriers of Biallelic TNNI3 Pathogenic Variants.

Janin A, Perouse de Montclos T, Nguyen K, Consolino E, Nadeau G, Rey G, Bouchot O, Blanchet P, Sabbagh Q, Cazeneuve C, El-Malti R, Morel E, Delinière A, Chevalier P, Millat G.

Mol Diagn Ther. 2022 Sep;26(5):551-560. doi: 10.1007/s40291-022-00604-3. Epub 2022 Jul 15.

PubMed [citation]
PMID:
35838873

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3.

Kühnisch J, Herbst C, Al-Wakeel-Marquard N, Dartsch J, Holtgrewe M, Baban A, Mearini G, Hardt J, Kolokotronis K, Gerull B, Carrier L, Beule D, Schubert S, Messroghli D, Degener F, Berger F, Klaassen S.

Clin Genet. 2019 Dec;96(6):549-559. doi: 10.1111/cge.13645. Epub 2019 Oct 22.

PubMed [citation]
PMID:
31568572
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004669680.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 927030). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys50Glufs*60) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNNI3 are known to be pathogenic (PMID: 35838873, 31568572, 34036930).

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

From All of Us Research Program, National Institutes of Health, SCV004821888.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Variant of Uncertain Significance due to insufficient evidence: This variant inserts 1 nucleotide in exon 4 of the TNNI3 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 assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Disease-causing variants in TNNI3 are mostly missense variants that act in a dominant-negative manner. The role of TNNI3 truncation variants in cardiomyopathy is not clearly established. Available evidence is insufficient to determine the role of this variant in disease conclusively.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Jan 19, 2025