rs869320739

Positions:

• chr2-178546110-G-C
• chr2-178546110-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001267550.2(TTN):​c.95126C>G​(p.Pro31709Arg) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 10.0

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 2-178546110-G-C is Pathogenic according to our data. Variant chr2-178546110-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178546110-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.95126C>G	p.Pro31709Arg	missense_variant	343/363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.95126C>G	p.Pro31709Arg	missense_variant	343/363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2016	The P29141R missense variant in the TTN gene has been reported previously in association with autosomal dominant hereditary myopathy with early respiratory failure (HMERF) (Palmio et al., 2014). Functional studies indicate that P29141R impairs the domain solubility and prevents proper protein folding (Hedberg et al., 2014). In these studies, the P29141R variant was reported as P30068R due to the use of alternative nomenclature. The P29141R variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P29141R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a conserved position predicted to be within the 119th fibronectin domain, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, P29141R is considered a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2019	- -

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

Pathogenic, no assertion criteria provided	literature only	GeneReviews	Feb 27, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 13, 2023	The TTN c.95126C>G (p.Pro31709Arg) missense variant results in the substitution of proline at amino acid position 31709 with arginine. This variant, sometimes referred to in the literature as c.90203C>G (p.Pro30068Arg), has been reported in a heterozygous state in two related individuals with myofibrillar myopathy with early respiratory failure (PMID: 23606733). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant is located in exon 343 of TTN, within the 119th fibronectin III domain of the titin A band motif, which is where all disease -causing variants have been located to date(PMID: 24575448). Functional studies in E. coli suggest that the c.95126C>G variant impairs domain solubility and prevents protein folding (PMID: 24636144). Another variant at the same position (c.95126C>A; p.Pro31709His) has been reported in an individual with myofibrillar myopathy with early respiratory failure (PMID: 30666435). Based on the available evidence, the c.95126C>G (p.Pro31709Arg) variant is classified as likely pathogenic for myofibrillar myopathy with early respiratory failure. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.94
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	4.0	.;.;.;H;.;.;H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.6	D;D;.;.;D;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;.;.;D;D;.
Polyphen		0.23	.;.;.;B;.;.;B
Vest4		0.60
MutPred		0.77		.;.;.;Gain of MoRF binding (P = 0.008);.;.;Gain of MoRF binding (P = 0.008);
MVP		0.36
MPC		0.13
ClinPred		0.74	D
GERP RS		4.9

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: rs869320739; hg19: chr2-179410837;