NM_001276345.2(TNNT2):c.299T>A (p.Ile100Asn) AND Hypertrophic cardiomyopathy 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 2, 2022
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:: RCV002273196.2

Allele description [Variation Report for NM_001276345.2(TNNT2):c.299T>A (p.Ile100Asn)]

NM_001276345.2(TNNT2):c.299T>A (p.Ile100Asn)

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.299T>A (p.Ile100Asn)

HGVS:

NC_000001.11:g.201365303A>T
NG_007556.1:g.17375T>A
NM_000364.4:c.299T>A
NM_001001430.3:c.269T>A
NM_001001431.3:c.269T>A
NM_001001432.3:c.254T>A
NM_001276345.2:c.299T>AMANE SELECT
NM_001276346.2:c.291+307T>A
NM_001276347.2:c.269T>A
NP_000355.2:p.Ile100Asn
NP_001001430.1:p.Ile90Asn
NP_001001431.1:p.Ile90Asn
NP_001001432.1:p.Ile85Asn
NP_001263274.1:p.Ile100Asn
NP_001263276.1:p.Ile90Asn
LRG_431t1:c.299T>A
LRG_431:g.17375T>A
LRG_431p1:p.Ile100Asn
NC_000001.10:g.201334431A>T
NM_001276345.1:c.299T>A

Protein change:

I100N

Links:

dbSNP: rs2102262330

NCBI 1000 Genomes Browser:

rs2102262330

Molecular consequence:

NM_001276346.2:c.291+307T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000364.4:c.299T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.269T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.269T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.254T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.299T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.269T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypertrophic cardiomyopathy 2
Synonyms:: Familial hypertrophic cardiomyopathy 2; TNNT2-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0007266; MedGen: C1861864; OMIM: 115195

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002557905	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18612386, 19061534, 23283745, 26507537, 27532257, 32098556, 33025817, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557905

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 2, 2022)

germline

clinical testing

PubMed (8)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy.

Ahmad F, Banerjee SK, Lage ML, Huang XN, Smith SH, Saba S, Rager J, Conner DA, Janczewski AM, Tobita K, Tinney JP, Moskowitz IP, Perez-Atayde AR, Keller BB, Mathier MA, Shroff SG, Seidman CE, Seidman JG.

PLoS One. 2008 Jul 9;3(7):e2642. doi: 10.1371/journal.pone.0002642.

PubMed [citation]

PMID:: 18612386
PMCID:: PMC2441440

Ile90Met, a novel mutation in the cardiac troponin T gene for familial hypertrophic cardiomyopathy in a Chinese pedigree.

Xu C, Wei M, Su B, Hua XW, Zhang GW, Xue XP, Pan CM, Liu R, Sheng Y, Lu ZG, Jin LR, Song HD.

Genet Res (Camb). 2008 Oct;90(5):445-50. doi: 10.1017/S0016672308009816.

PubMed [citation]

PMID:: 19061534

See all PubMed Citations (8)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557905.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, e.g., the variant, p.(Arg92Gln), has been reported to cause both DCM and HCM, even within the same family (PMID: 26507537). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Other missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ile100Met) is classified as a VUS in ClinVar for cardiomyopathy; however, it has been reported in one individual with HCM (PMID: 23283745) and also shown to segregate with disease (HCM) in a large multigenerational Chinese family (PMID: 19061534). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in an individual with HCM (PMID: 27532257). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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