2-178554127-C-T

Variant names:

• chr2-178554127-C-T
• rs187460377
• NM_001267550.2:c.88984G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.88984G>A​(p.Gly29662Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000719 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 6.15
• Publications: 1 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09341228).
• BP6: Variant 2-178554127-C-T is Benign according to our data. Variant chr2-178554127-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178174.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.88984G>A	p.Gly29662Ser	missense	Exon 333 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.84061G>A	p.Gly28021Ser	missense	Exon 283 of 313	NP_001243779.1
	TTN	NM_133378.4		c.81280G>A	p.Gly27094Ser	missense	Exon 282 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.88984G>A	p.Gly29662Ser	missense	Exon 333 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.88828G>A	p.Gly29610Ser	missense	Exon 331 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.88708G>A	p.Gly29570Ser	missense	Exon 331 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000214 AC: 53 AN: 247852 AF XY: 0.000171

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000595 AC: 87 AN: 1461564 Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38 AN XY: 727066

African (AFR) AF: 0.000657 AC: 22 AN: 33470

American (AMR) AF: 0.000447 AC: 20 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111774

Other (OTH) AF: 0.0000663 AC: 4 AN: 60370

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74432

African (AFR) AF: 0.000481 AC: 20 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000232 AC: 28

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Apr 09, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 23, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TTN c.88984G>A, p.Gly29662Ser variant [(rs187460377; ClinVar Variation ID: 178174) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Gly29662Ser variant cannot be determined with certainty.

Jul 15, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28704380)

not specified Uncertain:1 Benign:1

Sep 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly27094Ser variant in TTN has been identified in our lab in 1 individual wi th infant-onset DCM. This variant has also been identified in 1/3844 African Ame rican chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS/) and in 1/122 African American chromosomes by the 1000 Genomes Projec t (dbSNP rs187460377). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summar y, the clinical significance of the Gly27094Ser variant is uncertain.

Jul 24, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.81280G>A (p.Gly27094Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00021 in 247852 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). c.81280G>A has been observed in two cases of sudden unexplained death, without strong evidence for causality (e.g. Suktitipat_2017, Campuzano_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 30086531, 28704380). ClinVar contains an entry for this variant (Variation ID: 178174). Based on the evidence outlined above, the variant was classified as likely benign.

Cardiovascular phenotype Uncertain:1

Nov 20, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G20597S variant (also known as c.61789G>A), located in coding exon 160 of the TTN gene, results from a G to A substitution at nucleotide position 61789. The glycine at codon 20597 is replaced by serine, an amino acid with similar properties. This alteration has been reported (as NM_001267550.1:c.88984G>A p.G29662S) in a sudden unexplained death case; however, clinical details were limited (Suktitipat B et al. PLoS ONE, 2017 Jul;12:e0180056). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Benign:1

Jun 26, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.95
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.093	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.41
MPC		0.46
ClinPred		0.12	T
GERP RS		5.6
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs187460377; hg19: chr2-179418854;