NM_001267550.2(TTN):c.102398T>C (p.Ile34133Thr) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Apr 9, 2025
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:: RCV002222619.2

Allele description [Variation Report for NM_001267550.2(TTN):c.102398T>C (p.Ile34133Thr)]

NM_001267550.2(TTN):c.102398T>C (p.Ile34133Thr)

Genes:

TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.102398T>C (p.Ile34133Thr)

Other names:

p.Ile31565Thr

HGVS:

NC_000002.12:g.178534217A>G
NG_011618.3:g.301586T>C
NG_051363.1:g.16391A>G
NM_001256850.1:c.97475T>C
NM_001267550.2:c.102398T>CMANE SELECT
NM_003319.4:c.75203T>C
NM_133378.4:c.94694T>C
NM_133432.3:c.75578T>C
NM_133437.4:c.75779T>C
NP_001243779.1:p.Ile32492Thr
NP_001254479.2:p.Ile34133Thr
NP_003310.4:p.Ile25068Thr
NP_596869.4:p.Ile31565Thr
NP_597676.3:p.Ile25193Thr
NP_597681.4:p.Ile25260Thr
LRG_391:g.301586T>C
NC_000002.11:g.179398944A>G
NM_001267550.2:c.102398T>C

Protein change:

I25068T

Links:

dbSNP: rs764179161

NCBI 1000 Genomes Browser:

rs764179161

Molecular consequence:

NM_001256850.1:c.97475T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.102398T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.75203T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.94694T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.75578T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.75779T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002500287	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV006068936	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 9, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002500287

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 9, 2022)

germline

clinical testing

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

Citation Link,

SCV006068936

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 9, 2025)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy.

Bagnall RD, Ingles J, Dinger ME, Cowley MJ, Ross SB, Minoche AE, Lal S, Turner C, Colley A, Rajagopalan S, Berman Y, Ronan A, Fatkin D, Semsarian C.

J Am Coll Cardiol. 2018 Jul 24;72(4):419-429. doi: 10.1016/j.jacc.2018.04.078.

PubMed [citation]

PMID:: 30025578

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500287.1

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

Description

Variant summary: TTN c.94694T>C (p.Ile31565Thr) results in a non-conservative amino acid change located in the M-band region (100% PSI score, corresponding to a constitutively expressed exon) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249066 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.94694T>C has been reported in the literature as a VUS in an asymptomatic (incidental) male with no FH of cardiomyopathy and an asymmetric septal pattern of hypertrophy who underwent whole genome analysis (WGS) following prior genetic testing on a 46 gene panel that had not established a molecular diagnosis (example, Bagnall_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic/Dilated Cardiomyopathy/Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV006068936.1

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

Description

BP1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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