NM_001267550.2(TTN):c.4480G>A (p.Gly1494Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 25, 2024
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:: RCV000696197.10

Allele description [Variation Report for NM_001267550.2(TTN):c.4480G>A (p.Gly1494Ser)]

NM_001267550.2(TTN):c.4480G>A (p.Gly1494Ser)

Genes:

TTN:titin [Gene - OMIM - HGNC]
LOC101927055:uncharacterized LOC101927055 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.4480G>A (p.Gly1494Ser)

HGVS:

NC_000002.12:g.178777704C>T
NG_011618.3:g.58099G>A
NM_001256850.1:c.4480G>A
NM_001267550.2:c.4480G>AMANE SELECT
NM_003319.4:c.4342G>A
NM_133378.4:c.4480G>A
NM_133379.5:c.4480G>A
NM_133432.3:c.4342G>A
NM_133437.4:c.4342G>A
NP_001243779.1:p.Gly1494Ser
NP_001254479.2:p.Gly1494Ser
NP_003310.4:p.Gly1448Ser
NP_596869.4:p.Gly1494Ser
NP_596870.2:p.Gly1494Ser
NP_597676.3:p.Gly1448Ser
NP_597681.4:p.Gly1448Ser
LRG_391:g.58099G>A
NC_000002.11:g.179642431C>T
NR_120594.1:n.779C>T

Protein change:

G1448S

Links:

dbSNP: rs774506028

NCBI 1000 Genomes Browser:

rs774506028

Molecular consequence:

NM_001256850.1:c.4480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.4480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.4342G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.4480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133379.5:c.4480G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.4342G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.4342G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_120594.1:n.779C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000824749	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 25, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17576681, 9536098, 25589632, 27493940, 32778822, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824749

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 25, 2024)

germline

clinical testing

PubMed (6)
[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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824749.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1494 of the TTN protein (p.Gly1494Ser). This variant also falls at the last nucleotide of exon 25, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 574295). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the Z band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). 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: Mar 11, 2025

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