NM_000363.5(TNNI3):c.568G>T (p.Asp190Tyr) AND Hypertrophic cardiomyopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 11, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000152073.6

Allele description [Variation Report for NM_000363.5(TNNI3):c.568G>T (p.Asp190Tyr)]

NM_000363.5(TNNI3):c.568G>T (p.Asp190Tyr)

Gene:

TNNI3:troponin I3, cardiac type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.42

Genomic location:

Preferred name:

NM_000363.5(TNNI3):c.568G>T (p.Asp190Tyr)

HGVS:

NC_000019.10:g.55151899C>A
NG_007866.2:g.10834G>T
NG_011829.2:g.2340G>T
NM_000363.5:c.568G>TMANE SELECT
NP_000354.4:p.Asp190Tyr
LRG_432t1:c.568G>T
LRG_432:g.10834G>T
LRG_679:g.2340G>T
NC_000019.9:g.55663267C>A
NM_000363.4:c.568G>T

Protein change:

D190Y

Links:

dbSNP: rs727503500

NCBI 1000 Genomes Browser:

rs727503500

Molecular consequence:

NM_000363.5:c.568G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000200711	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jul 11, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12531876, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000200711

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jul 11, 2019)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.

Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ.

J Clin Invest. 2003 Jan;111(2):209-16. Erratum in: J Clin Invest. 2003 Mar;111(6):925.

PubMed [citation]

PMID:: 12531876
PMCID:: PMC151864

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000200711.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Asp190Tyr variant in TNNI3 has been identified by our laboratory in 1 adult with HCM and segregated with disease in 4 affected relatives. It was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another HCM-associated variant meeting our criteria for pathogenicity has been reported at this same position (p.Asp190Gly; Mogensen 2003) suggesting that variation at this amino acid may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp190Tyr variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2, PM5, PP1, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		5	not provided	1	not provided

Last Updated: Dec 24, 2022

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