NM_001267550.2(TTN):c.97099C>T (p.Arg32367Cys) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 2, 2022
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:: RCV000040848.12

Allele description [Variation Report for NM_001267550.2(TTN):c.97099C>T (p.Arg32367Cys)]

NM_001267550.2(TTN):c.97099C>T (p.Arg32367Cys)

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.97099C>T (p.Arg32367Cys)

Other names:

p.R30726C:CGT>TGT

HGVS:

NC_000002.12:g.178542755G>A
NG_011618.3:g.293048C>T
NG_051363.1:g.24929G>A
NM_001256850.1:c.92176C>T
NM_001267550.2:c.97099C>TMANE SELECT
NM_003319.4:c.69904C>T
NM_133378.4:c.89395C>T
NM_133432.3:c.70279C>T
NM_133437.4:c.70480C>T
NP_001243779.1:p.Arg30726Cys
NP_001254479.2:p.Arg32367Cys
NP_003310.4:p.Arg23302Cys
NP_596869.4:p.Arg29799Cys
NP_597676.3:p.Arg23427Cys
NP_597681.4:p.Arg23494Cys
LRG_391:g.293048C>T
NC_000002.11:g.179407482G>A
c.89395C>T

Protein change:

R23302C

Links:

dbSNP: rs202064385

NCBI 1000 Genomes Browser:

rs202064385

Molecular consequence:

NM_001256850.1:c.92176C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.97099C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.69904C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.89395C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.70279C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.70480C>T - 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
SCV000064539	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 29, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000237826	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Mar 1, 2017)	germline	clinical testing	Citation Link,
SCV002074265	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jan 2, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000064539

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 29, 2015)

germline

clinical testing

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

SCV000237826

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Mar 1, 2017)

germline

clinical testing

Citation Link,

SCV002074265

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jan 2, 2022)

germline

clinical testing

Citation Link

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	5	5	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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064539.6

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

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Arg29799Cys v ariant in TTN has been identified by our laboratory in 1 individual with ARVC an d 2 individuals with DCM, 1 of whom carried variants in another gene that were s ufficient to explain their disease. This variant has also been identified in 0.2 % (25/16628) of South Asian chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs202064385). Arginine (Arg) at positio n 29799 is conserved in mammals but not in evolutionarily distant species, and 2 fish species carry a cysteine (Cys) at this position, raising the possibility t hat this change may be tolerated. In summary, while the clinical significance of the p.Arg29799Cys variant is uncertain, its frequency and lack of conservation suggests that it is more likely to be benign.

#	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		5	not provided	5	not provided

From GeneDx, SCV000237826.3

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074265.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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