NM_001267550.2(TTN):c.96506T>C (p.Leu32169Pro) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 20, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001963337.4

Allele description [Variation Report for NM_001267550.2(TTN):c.96506T>C (p.Leu32169Pro)]

NM_001267550.2(TTN):c.96506T>C (p.Leu32169Pro)

Genes:

LOC126806421:CDK7 strongly-dependent group 2 enhancer GRCh37_chr2:179407630-179408829 [Gene]
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.96506T>C (p.Leu32169Pro)

HGVS:

NC_000002.12:g.178543467A>G
NG_011618.3:g.292336T>C
NG_051363.1:g.25641A>G
NM_001256850.1:c.91583T>C
NM_001267550.2:c.96506T>CMANE SELECT
NM_003319.4:c.69311T>C
NM_133378.4:c.88802T>C
NM_133432.3:c.69686T>C
NM_133437.4:c.69887T>C
NP_001243779.1:p.Leu30528Pro
NP_001254479.2:p.Leu32169Pro
NP_003310.4:p.Leu23104Pro
NP_596869.4:p.Leu29601Pro
NP_597676.3:p.Leu23229Pro
NP_597681.4:p.Leu23296Pro
LRG_391:g.292336T>C
NC_000002.11:g.179408194A>G

Protein change:

L23104P

Links:

dbSNP: rs2154143527

NCBI 1000 Genomes Browser:

rs2154143527

Molecular consequence:

NM_001256850.1:c.91583T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.96506T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.69311T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.88802T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.69686T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.69887T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dilated cardiomyopathy 1G (CMD1G)
Identifiers:: MONDO: MONDO:0011400; MedGen: C1858763; Orphanet: 154; OMIM: 604145

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2J (LGMDR10)
Synonyms:: Limb-girdle muscular dystrophy, type 2J; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 10
Identifiers:: MONDO: MONDO:0012127; MedGen: C1837342; Orphanet: 140922; OMIM: 608807

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002241610	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 20, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25589632, 23975875, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002241610

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 20, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, et al.

Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.

PubMed [citation]

PMID:: 25589632
PMCID:: PMC4560092

Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy.

Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET, Swanson LC, Soemedi R, Vasli N, Iannaccone ST, Shieh PB, Shur N, Dennison JM, Lawlor MW, Laporte J, Markianos K, Fairbrother WG, Granzier H, Beggs AH.

Neurology. 2013 Oct 1;81(14):1205-14. doi: 10.1212/WNL.0b013e3182a6ca62. Epub 2013 Aug 23.

PubMed [citation]

PMID:: 23975875
PMCID:: PMC3795603

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002241610.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 32169 of the TTN protein (p.Leu32169Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TTN-related neuromuscular conditions (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Dec 24, 2023

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