NM_001267550.2(TTN):c.48727C>T (p.Pro16243Ser) AND not specified

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Aug 17, 2020
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:: RCV000040294.31

Allele description [Variation Report for NM_001267550.2(TTN):c.48727C>T (p.Pro16243Ser)]

NM_001267550.2(TTN):c.48727C>T (p.Pro16243Ser)

Genes:

LOC126806426:BRD4-independent group 4 enhancer GRCh37_chr2:179478848-179480047 [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.48727C>T (p.Pro16243Ser)

Other names:

p.P14602S:CCC>TCC

HGVS:

NC_000002.12:g.178614880G>A
NG_011618.3:g.220923C>T
NG_051363.1:g.97054G>A
NM_001256850.1:c.43804C>T
NM_001267550.2:c.48727C>TMANE SELECT
NM_003319.4:c.21532C>T
NM_133378.4:c.41023C>T
NM_133432.3:c.21907C>T
NM_133437.4:c.22108C>T
NP_001243779.1:p.Pro14602Ser
NP_001254479.2:p.Pro16243Ser
NP_003310.4:p.Pro7178Ser
NP_596869.4:p.Pro13675Ser
NP_596869.4:p.Pro13675Ser
NP_597676.3:p.Pro7303Ser
NP_597681.4:p.Pro7370Ser
LRG_391:g.220923C>T
NC_000002.11:g.179479607G>A
c.41023C>T

Protein change:

P13675S

Links:

dbSNP: rs72677242

NCBI 1000 Genomes Browser:

rs72677242

Molecular consequence:

NM_001256850.1:c.43804C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.48727C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.21532C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.41023C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.21907C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.22108C>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
SCV000063985	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Jan 30, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000336577	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Benign (Oct 15, 2015)	germline	clinical testing	Citation Link,
SCV001432108	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 17, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000063985

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Benign
(Jan 30, 2013)

germline

clinical testing

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

SCV000336577

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Benign
(Oct 15, 2015)

germline

clinical testing

Citation Link,

SCV001432108

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 17, 2020)

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	not provided	12	12	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000063985.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	12	not provided	not provided	clinical testing	PubMed (1)

Description

Pro13675Ser in exon 209 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (27/8278) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS), as well as in 2.7% (5/186) of Finnish chromosomes from broad population by the 1000 Genomes Project (dbSNP rs72677242).

#	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		12	not provided	12	not provided

From Eurofins Ntd Llc (ga), SCV000336577.3

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001432108.1

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

Description

Variant summary: TTN c.41023C>T (p.Pro13675Ser) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 192712 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 8.62 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.41023C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. (benign n=7, VUS n=1). Based on the evidence outlined above, the variant was classified as 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: Apr 20, 2024

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