2-178546049-C-G

Variant names:

• chr2-178546049-C-G
• rs869320742
• NM_001267550.2:c.95187G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM5 PP3_Strong PP5_Very_Strong

The NM_001267550.2(TTN):​c.95187G>C​(p.Trp31729Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000322335: Functional studies indicate the variant impairs the domain solubility and prevents proper protein folding (Hedberg et al., 2014)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W31729L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91
• Publications: 6 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322335: Functional studies indicate the variant impairs the domain solubility and prevents proper protein folding (Hedberg et al., 2014); PMID: 24980681, 24575448, 24636144, 29382405, 30666435, 23606733, 29997562; SCV001578880: Experimental studies have shown that this missense change affects TTN function (PMID: 24636144).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-178546050-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 132135.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-178546049-C-G is Pathogenic according to our data. Variant chr2-178546049-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.95187G>C	p.Trp31729Cys	missense	Exon 343 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.90264G>C	p.Trp30088Cys	missense	Exon 293 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.87483G>C	p.Trp29161Cys	missense	Exon 292 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.95187G>C	p.Trp31729Cys	missense	Exon 343 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.95031G>C	p.Trp31677Cys	missense	Exon 341 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.94911G>C	p.Trp31637Cys	missense	Exon 341 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461442 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111714

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
1	-	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Benign	0.96
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.88		Loss of catalytic residue at A30087 (P = 0.0477)
MVP		0.91
MPC		0.58
ClinPred		1.0	D
GERP RS		5.8
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs869320742; hg19: chr2-179410776;