NM_001267550.2(TTN):c.90638T>C (p.Ile30213Thr) AND not specified

Germline classification:: Benign (7 submissions)
Last evaluated:: Nov 21, 2021
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:: RCV000154640.21

Allele description [Variation Report for NM_001267550.2(TTN):c.90638T>C (p.Ile30213Thr)]

NM_001267550.2(TTN):c.90638T>C (p.Ile30213Thr)

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.90638T>C (p.Ile30213Thr)

HGVS:

NC_000002.12:g.178552262A>G
NG_011618.3:g.283541T>C
NG_051363.1:g.34436A>G
NM_001256850.1:c.85715T>C
NM_001267550.2:c.90638T>CMANE SELECT
NM_003319.4:c.63443T>C
NM_133378.4:c.82934T>C
NM_133432.3:c.63818T>C
NM_133437.4:c.64019T>C
NP_001243779.1:p.Ile28572Thr
NP_001254479.1:p.Ile30213Thr
NP_001254479.2:p.Ile30213Thr
NP_003310.4:p.Ile21148Thr
NP_596869.4:p.Ile27645Thr
NP_597676.3:p.Ile21273Thr
NP_597681.4:p.Ile21340Thr
LRG_391t1:c.90638T>C
LRG_391:g.283541T>C
LRG_391p1:p.Ile30213Thr
NC_000002.11:g.179416989A>G
NM_001267550.1:c.90638T>C
NM_133379.3:c.*193323T>C

Protein change:

I21148T

Links:

dbSNP: rs114026724

NCBI 1000 Genomes Browser:

rs114026724

Molecular consequence:

NM_001256850.1:c.85715T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.90638T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.63443T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.82934T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.63818T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.64019T>C - 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
SCV000153382	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Nov 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000169409	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Apr 7, 2014)	germline	clinical testing	Citation Link,
SCV000204315	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Aug 11, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001361791	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Nov 6, 2019)	germline	clinical testing	Citation Link,
SCV001923195	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001951145	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001966716	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	15	15	not provided	not provided	not provided	clinical testing
not provided	germline	no	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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 Genetic Services Laboratory, University of Chicago, SCV000153382.2

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000169409.10

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204315.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	PubMed (1)

Description

Ile27645Thr in exon 284 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 2% (75/3932) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs114026724).

#	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		15	not provided	15	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361791.1

#	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.82934T>C (p.Ile27645Thr) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 248074 control chromosomes, predominantly at a frequency of 0.022 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 35-folds over the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.82934T>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with another pathogenic variant has been internally reported (TTR c.424G>A, p.V142I), providing supporting evidence for a benign role. Three ClinVar submitters (evaluation after 2014) cite the variant as benign. 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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001923195.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001951145.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001966716.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

Relating variation to medicine