NM_001267550.2(TTN):c.97198C>A (p.Pro32400Thr) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (3 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:: RCV000222441.10

Allele description [Variation Report for NM_001267550.2(TTN):c.97198C>A (p.Pro32400Thr)]

NM_001267550.2(TTN):c.97198C>A (p.Pro32400Thr)

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.97198C>A (p.Pro32400Thr)

HGVS:

NC_000002.12:g.178542558G>T
NG_011618.3:g.293245C>A
NG_051363.1:g.24732G>T
NM_001256850.1:c.92275C>A
NM_001267550.2:c.97198C>AMANE SELECT
NM_003319.4:c.70003C>A
NM_133378.4:c.89494C>A
NM_133432.3:c.70378C>A
NM_133437.4:c.70579C>A
NP_001243779.1:p.Pro30759Thr
NP_001254479.2:p.Pro32400Thr
NP_003310.4:p.Pro23335Thr
NP_596869.4:p.Pro29832Thr
NP_597676.3:p.Pro23460Thr
NP_597681.4:p.Pro23527Thr
LRG_391:g.293245C>A
NC_000002.11:g.179407285G>T
NM_003319.4:c.70003C>A

Protein change:

P23335T

Links:

dbSNP: rs373876117

NCBI 1000 Genomes Browser:

rs373876117

Molecular consequence:

NM_001256850.1:c.92275C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.97198C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.70003C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.89494C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.70378C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.70579C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000272811	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 30, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004813382	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25447171, 27930701, 36693943 Citation Link,
SCV006069952	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

SCV000272811

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Mar 30, 2015)

germline

clinical testing

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

SCV004813382

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 5, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV006069952

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	not provided	1	1	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

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

Post-mortem genetic analysis in juvenile cases of sudden cardiac death.

Campuzano O, Sanchez-Molero O, Allegue C, Coll M, Mademont-Soler I, Selga E, Ferrer-Costa C, Mates J, Iglesias A, Sarquella-Brugada G, Cesar S, Brugada J, Castellà J, Medallo J, Brugada R.

Forensic Sci Int. 2014 Dec;245:30-7. doi: 10.1016/j.forsciint.2014.10.004. Epub 2014 Oct 14.

PubMed [citation]

PMID:: 25447171

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272811.3

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

Description

The p.Pro29832Thr variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/11470 of Latino chromosomes a nd 10/65646 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs373876117). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro29832Thr varia nt is uncertain.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813382.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: TTN c.89494C>A (p.Pro29832Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 242672 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00012 vs 0.00039), allowing no conclusion about variant significance. c.89494C>A has been reported in the literature in individuals affected with sudden cardiac death or sudden unexplained death with other co-occurring variants (Campuzano_2014, Sanchez_2016, Martinez_2023). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25447171, 36693943, 27930701). ClinVar contains an entry for this variant (Variation ID: 229551). 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, SCV006069952.1

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

Description

BS1;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 25, 2025

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