NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 6, 2023
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:: RCV000806331.7

Allele description [Variation Report for NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs)]

NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs)

Genes:

LOC129935182:ATAC-STARR-seq lymphoblastoid active region 16807 [Gene]
TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.106114_106115dup (p.Leu35372fs)

HGVS:

NC_000002.12:g.178530500_178530501dup
NG_011618.3:g.305302_305303dup
NG_051363.1:g.12674_12675dup
NM_001256850.1:c.101191_101192dup
NM_001267550.2:c.106114_106115dupMANE SELECT
NM_003319.4:c.78919_78920dup
NM_133378.4:c.98410_98411dup
NM_133432.3:c.79294_79295dup
NM_133437.4:c.79495_79496dup
NP_001243779.1:p.Leu33731fs
NP_001254479.2:p.Leu35372fs
NP_003310.4:p.Leu26307fs
NP_596869.4:p.Leu32804fs
NP_597676.3:p.Leu26432fs
NP_597681.4:p.Leu26499fs
LRG_391:g.305302_305303dup
NC_000002.11:g.179395226_179395227insAA
NC_000002.11:g.179395227_179395228dup
NM_001267550.2:c.106114_106115dupTTMANE SELECT
NM_003319.4:c.78919_78920dupTT

Protein change:

L26307fs

Links:

dbSNP: rs1394131775

NCBI 1000 Genomes Browser:

rs1394131775

Molecular consequence:

NM_001256850.1:c.101191_101192dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001267550.2:c.106114_106115dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003319.4:c.78919_78920dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133378.4:c.98410_98411dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133432.3:c.79294_79295dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_133437.4:c.79495_79496dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000946323	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 6, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26735901, 25589632, 18948003, 23975875, 24395473, 27869827, 32964742, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000946323

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 6, 2023)

germline

clinical testing

PubMed (8)
[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

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, et al.

N Engl J Med. 2016 Jan 21;374(3):233-41. doi: 10.1056/NEJMoa1505517. Epub 2016 Jan 6.

PubMed [citation]

PMID:: 26735901
PMCID:: PMC4797319

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

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000946323.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Leu35372Phefs*34) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with peripartum cardiomyopathy (PMID: 26735901). ClinVar contains an entry for this variant (Variation ID: 651058). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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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