rs397517499

Variant names:

• chr2-178790088-C-A
• rs397517499
• NM_001267550.2:c.1828G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178790088-C-A
• chr2-178790088-C-G
• chr2-178790088-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001267550.2(TTN):​c.1828G>T​(p.Val610Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V610V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.82
• Publications: 5 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3524642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.1828G>T	p.Val610Leu	missense_variant	Exon 12 of 363	ENST00000589042.5	NP_001254479.2
TTN	NM_133379.5	c.1828G>T	p.Val610Leu	missense_variant	Exon 12 of 46	ENST00000360870.10	NP_596870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.1828G>T	p.Val610Leu	missense_variant	Exon 12 of 363	5	NM_001267550.2	ENSP00000467141.1
TTN	ENST00000360870.10	c.1828G>T	p.Val610Leu	missense_variant	Exon 12 of 46	5	NM_133379.5	ENSP00000354117.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250960 AF XY: 0.00000737

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460648 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726644

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111324

Other (OTH) AF: 0.0000331 AC: 2 AN: 60340

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.97
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D;D;.;D;D;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
PhyloP100		2.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N;N;.;.;N;N;.;N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;.;.;D;D;.;D
Sift4G	Benign	0.075	.;.;.;.;.;.;.;T
Polyphen		0.99, 1.0	.;.;.;D;.;.;D;D
Vest4		0.19
MutPred		0.59		Loss of helix (P = 0.0041);.;Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);.;.;Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);
MVP		0.62
MPC		0.46
ClinPred		0.63	D
GERP RS		5.6
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397517499; hg19: chr2-179654815;