NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000255593.17

Allele description [Variation Report for NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter)]

NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter)

Genes:

LOC126806423:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179443309-179444508 [Gene]
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.67495C>T (p.Arg22499Ter)

HGVS:

NC_000002.12:g.178579702G>A
NG_011618.3:g.256101C>T
NG_051363.1:g.61876G>A
NM_001256850.1:c.62572C>T
NM_001267550.2:c.67495C>TMANE SELECT
NM_003319.4:c.40300C>T
NM_133378.4:c.59791C>T
NM_133432.3:c.40675C>T
NM_133437.4:c.40876C>T
NP_001243779.1:p.Arg20858Ter
NP_001254479.2:p.Arg22499Ter
NP_003310.4:p.Arg13434Ter
NP_596869.4:p.Arg19931Ter
NP_597676.3:p.Arg13559Ter
NP_597681.4:p.Arg13626Ter
LRG_391t1:c.67495C>T
LRG_391:g.256101C>T
NC_000002.11:g.179444429G>A
NM_001267550.1:c.67495C>T
NM_003319.4:c.40300C>T

Protein change:

R13434*

Links:

dbSNP: rs574660186

NCBI 1000 Genomes Browser:

rs574660186

Molecular consequence:

NM_001256850.1:c.62572C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001267550.2:c.67495C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003319.4:c.40300C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133378.4:c.59791C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133432.3:c.40675C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_133437.4:c.40876C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322336	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 25, 2024)	germline	clinical testing	Citation Link,
SCV000338691	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Likely pathogenic (Jun 14, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000928048	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Nov 13, 2018)	germline	clinical testing	Citation Link,
SCV001879686	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Dec 23, 2020)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25589632, 22335739, 27437901, 27437900, 26467025
SCV002022473	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 23, 2021)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, et al.

Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.

PubMed [citation]

PMID:: 25589632
PMCID:: PMC4560092

Truncations of titin causing dilated cardiomyopathy.

Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, et al.

N Engl J Med. 2012 Feb 16;366(7):619-28. doi: 10.1056/NEJMoa1110186.

PubMed [citation]

PMID:: 22335739
PMCID:: PMC3660031

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000322336.9

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

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25589632, 27625338, 33534821, 33906374, 22335739, 36264615, 35177841, 31691645, 36396199, 35629941, 34935411, 25326635, 27437901, 33226272, 39310445, 39020067)

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

From Eurofins Ntd Llc (ga), SCV000338691.5

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

#	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		2	not provided	not provided	not provided

From Blueprint Genetics, SCV000928048.2

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

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

From Athena Diagnostics, SCV001879686.1

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

Description

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant occurs in the A-band of the TTN gene, and is a nonsense variant in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). Truncating variants in TTN occur significantly more often in the A-band of cardiomyopathy patients, and in the M-band of muscular dystrophy patients, compared to the general population (PMID: 255289632). Nonsense and other truncating variants in TTN have been reported in patients with dominant cardiomyopathy, dominant tibial muscular dystrophy, recessive salih myopathy, recessive limb-girdle muscular dystrophy, and recessive centronuclear myopathy (OMIM# 188840). However, these types of variants have also been found in healthy individuals (PMID: 25589632). This variant has been identified in at least one individual with dilated cardiomyopathy (DCM) (PMID: 22335739, 25589632).

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

From Revvity Omics, Revvity, SCV002022473.3

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

#	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: May 3, 2025

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