rs869320740

Variant names:

• chr2-178546102-A-G
• rs869320740
• NM_001267550.2:c.95134T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 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 (★★). ClinVar reports functional evidence for this variant: "SCV004047115: 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)." and additional evidence is available in ClinVar. 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:15 O:1
• Conservation: PhyloP100: 6.08
• Publications: 32 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004047115: 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).; SCV000322332: Published functional studies demonstrate that C30071R impairs solubility of the 119th fibronectin-3 domain, causing defective protein folding (Hedberg et al., 2014);; SCV000543100: Experimental studies have shown that this missense change affects TTN function (PMID: 24636144).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-178546102-A-G is Pathogenic according to our data. Variant chr2-178546102-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132133.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.95134T>C	p.Cys31712Arg	missense	Exon 343 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.90211T>C	p.Cys30071Arg	missense	Exon 293 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.87430T>C	p.Cys29144Arg	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.95134T>C	p.Cys31712Arg	missense	Exon 343 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.94978T>C	p.Cys31660Arg	missense	Exon 341 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.94858T>C	p.Cys31620Arg	missense	Exon 341 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243382 AF XY: 0.00000758

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85500

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108116

Other (OTH) AF: 0.0000166 AC: 1 AN: 60132

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
3	-	-	Myopathy, myofibrillar, 9, with early respiratory failure (4)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.79
Sift	Benign	0.047	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.55		Gain of disorder (P = 0.0059)
MVP		0.64
MPC		0.55
ClinPred		0.74	D
GERP RS		5.8
Mutation Taster		=1/99	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: rs869320740; hg19: chr2-179410829;