rs869320740

Positions:

• chr2-178546102-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_001267550.2(TTN):​c.95134T>C​(p.Cys31712Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,455,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C31712W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 6.08

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TTN
• PP5: Variant 2-178546102-A-G is Pathogenic according to our data. Variant chr2-178546102-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178546102-A-G is described in Lovd as [Pathogenic]. Variant chr2-178546102-A-G is described in Lovd as [Pathogenic]. Variant chr2-178546102-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.95134T>C	p.Cys31712Arg	missense_variant	343/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2043+3741A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.95134T>C	p.Cys31712Arg	missense_variant	343/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.416+22466A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243382 Hom.: 0 AF XY: 0.00000758 AC XY: 1 AN XY: 131866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1455650 Hom.: 0 Cov.: 33 AF XY: 0.00000415 AC XY: 3 AN XY: 723540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	Published functional studies demonstrate a that C30071R impairs solubility of the 119th fibronectin-3 domain, causing defective protein folding (Hedberg et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32039858, 27854229, 22577215, 24636144, 24444549, 29435569, 23514108, 25500009, 22577218, 30666435, 24980681, 24575448, 26518445, 26269091, 25253871, 32403337, 32307395) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	TTN: PP1:Strong, PM1, PM2, PM5, PP4, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2017	- -

Myopathy, myofibrillar, 9, with early respiratory failure Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The TTN c.95134T>C variant has been reported in heterozygous state in individuals affected with Myopathy, myofibrillar, 9, with early respiratory failure (Chauveau et. al., 2014; Pfeffer et. al., 2014). It is a common cause of HMERF in individuals of many different ancestries (Pfeffer et. al., 2014, Yue et. al., 2015). Experimental studies have found that this missense change may interfere with the proper folding of the fibronectin III domain 119 of the TTN protein (Hedberg et. al., 2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Cys31712Arg variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.0004109% in gnomAD database. The amino acid Cys at position 31712 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

This variant is also known as g.274375T4C (p.Cys30071Arg). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 31712 of the TTN protein (p.Cys31712Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant hereditary myopathy with early respiratory failure (HMERF) (PMID: 24444549, 24980681, 25500009). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132133). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TTN function (PMID: 24636144). 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. -

Dilated cardiomyopathy 1G Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 23, 2017

- -

Hypertrophic cardiomyopathy 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000132133) and a different missense change at the same codon (p.Cys31712Tyr) has been reported to be associated with TTN related disorder (PMID: 25253871). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23514108, 24444549, 25500009). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.95
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T;T;T;.;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.2	D;D;.;.;D;D;.
REVEL	Pathogenic	0.79
Sift	Benign	0.047	D;T;.;.;T;T;.
Polyphen		1.0	.;.;.;D;.;.;D
Vest4		0.66
MutPred		0.55		.;.;.;Gain of disorder (P = 0.0059);.;.;Gain of disorder (P = 0.0059);
MVP		0.64
MPC		0.55
ClinPred		0.74	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: rs869320740; hg19: chr2-179410829;