rs201047740

chr2-178751755-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_133379.5(TTN):c.10645C>T(p.Arg3549Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000118 in 1,612,964 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3549H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.29

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_133379.5	c.10645C>T	p.Arg3549Cys	missense_variant	46/46	ENST00000360870.10
TTN	NM_001267550.2	c.11311+1369C>T		intron_variant		ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10	c.10645C>T	p.Arg3549Cys	missense_variant	46/46	5	NM_133379.5
TTN	ENST00000589042.5	c.11311+1369C>T		intron_variant		5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.1224-4511G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 250126 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135168

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461084 Hom.: 0 Cov.: 39 AF XY: 0.000105 AC XY: 76 AN XY: 726826

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151880 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74172

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000422 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2013	The Arg3549Cys variant in TTN has not been reported in individuals with cardiomy opathy or in large population studies. Computational analyses are limited or una vailable for this variant. Additional information is needed to fully assess the clinical significance of the Arg3549Cys variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2015	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM-CRDM panel(s). -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.12	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.71
MVP		0.71
ClinPred		0.17	T
GERP RS		5.0

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: rs201047740; hg19: chr2-179616482; COSMIC: COSV60013858; COSMIC: COSV60013858;