NM_001267550.2(TTN):c.83315A>T (p.Asn27772Ile) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Nov 29, 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:: RCV000220460.15

Allele description [Variation Report for NM_001267550.2(TTN):c.83315A>T (p.Asn27772Ile)]

NM_001267550.2(TTN):c.83315A>T (p.Asn27772Ile)

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.83315A>T (p.Asn27772Ile)

Other names:

p.N26131I:AAT>ATT

HGVS:

NC_000002.12:g.178562817T>A
NG_011618.3:g.272986A>T
NG_051363.1:g.44991T>A
NM_001256850.1:c.78392A>T
NM_001267550.2:c.83315A>TMANE SELECT
NM_003319.4:c.56120A>T
NM_133378.4:c.75611A>T
NM_133432.3:c.56495A>T
NM_133437.4:c.56696A>T
NP_001243779.1:p.Asn26131Ile
NP_001254479.2:p.Asn27772Ile
NP_003310.4:p.Asn18707Ile
NP_596869.4:p.Asn25204Ile
NP_597676.3:p.Asn18832Ile
NP_597681.4:p.Asn18899Ile
LRG_391t1:c.83315A>T
LRG_391:g.272986A>T
NC_000002.11:g.179427544T>A
NM_001267550.1:c.83315A>T
NM_003319.4:c.56120A>T

Protein change:

N18707I

Links:

dbSNP: rs578191491

NCBI 1000 Genomes Browser:

rs578191491

Molecular consequence:

NM_001256850.1:c.78392A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.83315A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.56120A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.75611A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.56495A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.56696A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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KTR2 [Candida albicans SC5314]
KTR2 [Candida albicans SC5314]
Gene ID:3645443

Gene
tigara TP53 induced glycolysis regulatory phosphatase a [Danio rerio]
tigara TP53 induced glycolysis regulatory phosphatase a [Danio rerio]
Gene ID:664696

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000228521	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Likely benign (Mar 6, 2018)	germline	clinical testing	Citation Link,
SCV000237646	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV000272779	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jun 11, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002034628	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
SCV002766505	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Nov 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26516846, 27854218 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	not provided	1	1	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	unknown	6	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

Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death.

Campuzano O, Sanchez-Molero O, Mademont-Soler I, Riuró H, Allegue C, Coll M, Pérez-Serra A, Mates J, Picó F, Iglesias A, Brugada R.

Int J Mol Sci. 2015 Oct 27;16(10):25773-87. doi: 10.3390/ijms161025773.

PubMed [citation]

PMID:: 26516846
PMCID:: PMC4632826

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000228521.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	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		6	not provided	not provided	not provided

From GeneDx, SCV000237646.4

#	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, SCV000272779.3

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

Description

The p.Asn25204Ile variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (14/11202) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs578191491). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Asn25204Ile 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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV002034628.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766505.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: TTN c.75611A>T (p.Asn25204Ile) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 150894 control chromosomes, predominantly at a frequency of 0.011 within the Latino subpopulation in the gnomAD database (v3.1, genomes dataset), including 5 homozygotes. The variant, c.75611A>T has been reported in the literature in an individual with muscle weakness (Campuzano_2015), and in several heterozygous individuals with various cardiac phenotypes (Punetha_2016), however without convincing evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), likely benign (n=3) / benign (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 13, 2024

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