rs727503536

Variant names:

• chr2-178535635-C-G
• rs727503536
• NM_001267550.2:c.100980G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178535635-C-G
• chr2-178535635-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001267550.2(TTN):​c.100980G>C​(p.Glu33660Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E33660V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.616
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096812814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.100980G>C	p.Glu33660Asp	missense_variant	Exon 358 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.100980G>C	p.Glu33660Asp	missense_variant	Exon 358 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461504 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111758

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000207 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu31092Asp variant in TTN has not been previously identified by our laborat ory, been reported in the literature, or identified in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignG VGD, PolyPhen2, and SIFT) suggest that the Glu31092Asp variant may not impact th e normal function of the protein. Many bird species have an Asp at this position of TTN, suggesting that this change might be tolerated. However, this informati on is not predictive enough to rule out pathogenicity. In summary, additional in formation is needed to fully assess the clinical significance of the Glu31092Asp variant. -

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

Feb 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 33660 of the TTN protein (p.Glu33660Asp). This variant is not present in population databases (gnomAD no frequency). 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: 165661). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.83
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.83	T;T;T;.;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.097	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.79	.;.;.;N;.;.;N
PhyloP100		0.62
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N;.;.;N;N;.
REVEL	Benign	0.064
Sift	Benign	0.067	T;T;.;.;T;T;.
Polyphen		0.0020	.;.;.;B;.;.;B
Vest4		0.083
MutPred		0.49		.;.;.;Loss of methylation at K32021 (P = 0.0831);.;.;Loss of methylation at K32021 (P = 0.0831);
MVP		0.26
MPC		0.077
ClinPred		0.23	T
GERP RS		3.5
Mutation Taster		=61/39	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: rs727503536; hg19: chr2-179400362;