NM_001267550.2(TTN):c.68165A>G (p.Asn22722Ser) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 9, 2024
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:: RCV000216817.5

Allele description [Variation Report for NM_001267550.2(TTN):c.68165A>G (p.Asn22722Ser)]

NM_001267550.2(TTN):c.68165A>G (p.Asn22722Ser)

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.68165A>G (p.Asn22722Ser)

HGVS:

NC_000002.12:g.178578865T>C
NG_011618.3:g.256938A>G
NG_051363.1:g.61039T>C
NM_001256850.1:c.63242A>G
NM_001267550.2:c.68165A>GMANE SELECT
NM_003319.4:c.40970A>G
NM_133378.4:c.60461A>G
NM_133432.3:c.41345A>G
NM_133437.4:c.41546A>G
NP_001243779.1:p.Asn21081Ser
NP_001254479.2:p.Asn22722Ser
NP_003310.4:p.Asn13657Ser
NP_596869.4:p.Asn20154Ser
NP_597676.3:p.Asn13782Ser
NP_597681.4:p.Asn13849Ser
LRG_391:g.256938A>G
NC_000002.11:g.179443592T>C
NM_001256850.1:c.63242A>G

Protein change:

N13657S

Links:

dbSNP: rs200493270

NCBI 1000 Genomes Browser:

rs200493270

Molecular consequence:

NM_001256850.1:c.63242A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.68165A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.40970A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.60461A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.41345A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.41546A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000272735	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Feb 12, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004804342	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jan 9, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272735

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Feb 12, 2015)

germline

clinical testing

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

SCV004804342

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jan 9, 2024)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

van Lint FHM, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH, Christiaans I.

Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.

PubMed [citation]

PMID:: 30847666
PMCID:: PMC6533346

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272735.3

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

Description

The p.Asn20154Ser variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 15/66666 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200493270). Computational prediction tools and conservation analysis suggest t hat the p.Asn20154Ser variant may impact the protein. However, none of these too ls are predictive enough to determine pathogenicity. In summary, the clinical si gnificance of the p.Asn20154Ser variant 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, SCV004804342.1

#	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.60461A>G (p.Asn20154Ser) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 248344 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. However, in certain ethnicities, e.g. in the Swedish, the variant is reported with an even higher frequency (i.e. 0.00046), and this frequency is higher than the estimated maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), suggesting that the variant might be benign. The variant, c.60461A>G, has been reported in the literature in individuals affected with cardiomyopathy (van Lint_2019), however no supportive evidence for causality was provided. This report does 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. ClinVar contains an entry for this variant (Variation ID: 229499). Based on the evidence outlined above, the variant was classified as likely 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: Mar 30, 2024

ClinVar

Relating variation to medicine