NM_001267550.2(TTN):c.87623A>T (p.Tyr29208Phe) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 30, 2021
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:: RCV000040734.13

Allele description [Variation Report for NM_001267550.2(TTN):c.87623A>T (p.Tyr29208Phe)]

NM_001267550.2(TTN):c.87623A>T (p.Tyr29208Phe)

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.87623A>T (p.Tyr29208Phe)

Other names:

p.Y27567F:TAC>TTC

HGVS:

NC_000002.12:g.178557731T>A
NG_011618.3:g.278072A>T
NG_051363.1:g.39905T>A
NM_001256850.1:c.82700A>T
NM_001267550.2:c.87623A>TMANE SELECT
NM_003319.4:c.60428A>T
NM_133378.4:c.79919A>T
NM_133432.3:c.60803A>T
NM_133437.4:c.61004A>T
NP_001243779.1:p.Tyr27567Phe
NP_001254479.2:p.Tyr29208Phe
NP_003310.4:p.Tyr20143Phe
NP_596869.4:p.Tyr26640Phe
NP_597676.3:p.Tyr20268Phe
NP_597681.4:p.Tyr20335Phe
LRG_391:g.278072A>T
NC_000002.11:g.179422458T>A
c.79919A>T

Protein change:

Y20143F

Links:

dbSNP: rs201831707

NCBI 1000 Genomes Browser:

rs201831707

Molecular consequence:

NM_001256850.1:c.82700A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.87623A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.60428A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.79919A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.60803A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.61004A>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
SCV000064425	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 10, 2012)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000237683	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jan 22, 2018)	germline	clinical testing	Citation Link,
SCV001821437	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 30, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24503780, 28611029 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000064425

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 10, 2012)

germline

clinical testing

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

SCV000237683

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Jan 22, 2018)

germline

clinical testing

Citation Link,

SCV001821437

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 30, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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	1	1	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

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.

Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH.

Genet Med. 2014 Aug;16(8):601-8. doi: 10.1038/gim.2013.204. Epub 2014 Feb 6.

PubMed [citation]

PMID:: 24503780

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064425.6

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

Description

The Tyr26640Phe variant (TTN) has not been reported in the literature, but has b een identified in 5/6690 European American chromosomes and 1/3224 African Americ an chromosomes from a broad, though clinically unspecified population (NHLBI Exo me Sequencing Project; http://evs.gs.washington.edu/EVS). Tyrosine (Tyr) at posi tion 26640 is highly conserved in mammals and across evolutionarily distant spec ies, increasing the likelihood that a change would not be tolerated. Computation al predictions on the impact to the protein are mixed (AlignGVGD, SIFT), though the accuracy of these tools is unknown. Additional data is needed to further ass ess the clinical significance of the Tyr26640Phe variant.

#	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 GeneDx, SCV000237683.8

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001821437.1

#	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.79919A>T (p.Tyr26640Phe) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 280402 control chromosomes, predominantly at a frequency of 0.00038 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), allowing no conclusion about variant significance. However, the variant is observed in North-western European subpopulation with an even higher frequency, 0.0006338, suggesting that the variant could be benign. c.79919A>T has been reported in the literature in 2 individuals affected with Dilated Cardiomyopathy (Pugh_2014, Haskell_2017). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, 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, and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly 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: Sep 29, 2024

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