NM_001267550.2(TTN):c.82691C>T (p.Ala27564Val) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 29, 2020
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:: RCV000040686.17

Allele description [Variation Report for NM_001267550.2(TTN):c.82691C>T (p.Ala27564Val)]

NM_001267550.2(TTN):c.82691C>T (p.Ala27564Val)

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.82691C>T (p.Ala27564Val)

Other names:

p.A25923V:GCG>GTG

HGVS:

NC_000002.12:g.178563441G>A
NG_011618.3:g.272362C>T
NG_051363.1:g.45615G>A
NM_001256850.1:c.77768C>T
NM_001267550.2:c.82691C>TMANE SELECT
NM_003319.4:c.55496C>T
NM_133378.4:c.74987C>T
NM_133432.3:c.55871C>T
NM_133437.4:c.56072C>T
NP_001243779.1:p.Ala25923Val
NP_001254479.2:p.Ala27564Val
NP_003310.4:p.Ala18499Val
NP_596869.4:p.Ala24996Val
NP_597676.3:p.Ala18624Val
NP_597681.4:p.Ala18691Val
LRG_391:g.272362C>T
NC_000002.11:g.179428168G>A
NM_003319.4:c.55496C>T
Q8WZ42:p.Ala25923Val
c.74987C>T

Protein change:

A18499V

Links:

UniProtKB: Q8WZ42#VAR_040270; dbSNP: rs55634791

NCBI 1000 Genomes Browser:

rs55634791

Molecular consequence:

NM_001256850.1:c.77768C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.82691C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.55496C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.74987C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.55871C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.56072C>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
SCV000064377	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jun 28, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001372336	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jun 29, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001920391	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

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000064377

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jun 28, 2017)

germline

clinical testing

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

SCV001372336

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jun 29, 2020)

germline

clinical testing

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

Citation Link,

SCV001920391

Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus

See additional submitters

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	yes	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	not provided	2	2	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

Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth.

Sahlin E, Gréen A, Gustavsson P, Liedén A, Nordenskjöld M, Papadogiannakis N, Pettersson K, Nilsson D, Jonasson J, Iwarsson E.

PLoS One. 2019;14(1):e0210017. doi: 10.1371/journal.pone.0210017.

PubMed [citation]

PMID:: 30615648
PMCID:: PMC6322759

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064377.6

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

Description

The p.Ala24996Val variant in TTN has been identified by our laboratory in 1 indi vidual with HCM, in 0.12% (155/125908) of European chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs55634791) and in ClinVar (Variant ID: 47416). Computational prediction tools and conservat ion analysis do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of the p.Ala24996Val variant is uncert ain.

#	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		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372336.1

#	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.74987C>T (p.Ala24996Val) results in a non-conservative amino acid change located in the A-band region 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 0.00065 in 248272 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of 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 Non-Finnish European origin. To our knowledge, the variant c.74987C>T, has not been reported in the literature in individuals affected with Cardiomyopathy, and no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. 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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001920391.1

#	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: Sep 29, 2024

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