NM_001267550.2(TTN):c.28070C>T (p.Thr9357Ile) AND not specified

Germline classification:: Benign/Likely benign (5 submissions)
Last evaluated:: Jun 16, 2022
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:: RCV000040076.27

Allele description [Variation Report for NM_001267550.2(TTN):c.28070C>T (p.Thr9357Ile)]

NM_001267550.2(TTN):c.28070C>T (p.Thr9357Ile)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.28070C>T (p.Thr9357Ile)

Other names:

p.T9040I:ACA>ATA

HGVS:

NC_000002.12:g.178711166G>A
NG_011618.3:g.124637C>T
NM_001256850.1:c.27119C>T
NM_001267550.2:c.28070C>TMANE SELECT
NM_003319.4:c.13282+26916C>T
NM_133378.4:c.24338C>T
NM_133432.3:c.13657+26916C>T
NM_133437.4:c.13858+26916C>T
NP_001243779.1:p.Thr9040Ile
NP_001254479.1:p.Thr9357Ile
NP_001254479.2:p.Thr9357Ile
NP_596869.4:p.Thr8113Ile
LRG_391t1:c.28070C>T
LRG_391:g.124637C>T
LRG_391p1:p.Thr9357Ile
NC_000002.11:g.179575893G>A
NM_001267550.1:c.28070C>T
NM_133379.3:c.*34419C>T
c.24338C>T

Protein change:

T8113I

Links:

dbSNP: rs144930507

NCBI 1000 Genomes Browser:

rs144930507

Molecular consequence:

NM_003319.4:c.13282+26916C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_133432.3:c.13657+26916C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_133437.4:c.13858+26916C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001256850.1:c.27119C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.28070C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.24338C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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Homo sapiens regucalcin (senescence marker protein-30) (RGN), mRNA
Homo sapiens regucalcin (senescence marker protein-30) (RGN), mRNA
gi|9665243|ref|NM_004683.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000063767	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (May 11, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000169663	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (May 7, 2014)	germline	clinical testing	Citation Link,
SCV000315450	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000336356	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Oct 20, 2015)	germline	clinical testing	Citation Link,
SCV002555952	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jun 16, 2022)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000063767.6

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

Description

p.Thr8113Ile in exon 94 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (51/9796) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP dbSNP rs144930507).

#	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, SCV000169663.11

#	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 PreventionGenetics, part of Exact Sciences, SCV000315450.1

#	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

From Eurofins Ntd Llc (ga), SCV000336356.3

#	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, SCV002555952.1

#	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.24338C>T (p.Thr8113Ile) results in a non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 248988 control chromosomes, predominantly at a frequency of 0.0054 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14 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 a benign polymorphism found primarily in populations of African or African-American origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=5, 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: Oct 20, 2024

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