2-178545864-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001267550.2(TTN):c.95372G>A(p.Gly31791Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31791A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.91

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001267550.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-178545865-C-G is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TTN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 2-178545864-C-T is Pathogenic according to our data. Variant chr2-178545864-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132139.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=2}. Variant chr2-178545864-C-T is described in Lovd as [Pathogenic]. Variant chr2-178545864-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.95372G>A	p.Gly31791Asp	missense_variant	343/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2043+3503C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.95372G>A	p.Gly31791Asp	missense_variant	343/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.416+22228C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32403337, 24575448, 23514108) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2023	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 31791 of the TTN protein (p.Gly31791Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary myopathy with early respiratory failure (PMID: 23514108, 25253871). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly30150Asp. ClinVar contains an entry for this variant (Variation ID: 132139). 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T;T;.;T;T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.2	D;D;.;.;D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D;.;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;D
Vest4		0.68
MutPred		0.76		.;.;.;Loss of catalytic residue at G30148 (P = 0.0683);.;.;Loss of catalytic residue at G30148 (P = 0.0683);
MVP		0.50
MPC		0.53
ClinPred		0.96	D
GERP RS		5.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs869320744; hg19: chr2-179410591;