rs202012910

Positions:

• chr2-178590316-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_001267550.2(TTN):​c.61409T>C​(p.Ile20470Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000649 in 1,570,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: 9.27

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.11688176).
• BP6: Variant 2-178590316-A-G is Benign according to our data. Variant chr2-178590316-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47173.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.61409T>C	p.Ile20470Thr	missense_variant	304/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.3189-823A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.61409T>C	p.Ile20470Thr	missense_variant	304/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-7280A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152010 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000108 AC: 23 AN: 213576 Hom.: 0 AF XY: 0.0000968 AC XY: 11 AN XY: 113650

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 65 AN: 1418454 Hom.: 0 Cov.: 36 AF XY: 0.0000485 AC XY: 34 AN XY: 700372

Gnomad4 AFR exome AF: 0.000900

Gnomad4 AMR exome AF: 0.0000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000293

Gnomad4 OTH exome AF: 0.0000513

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74352

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.000511 AC: 2

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TTN p.I17902T variant was not identified in the literature but was identified in dbSNP (ID: rs202012910) and ClinVar (classified as uncertain significance by Invitae, GeneDx and five other laboratories). The variant was identified in control databases in 30 of 244940 chromosomes at a frequency of 0.0001225 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.I17902 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 10, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 25, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	The TTN c.61409T>C; p.Ile20470Thr variant (rs202012910; ClinVar Variation ID: 47173) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Ile20470Thr variant cannot be determined with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2019	This variant is associated with the following publications: (PMID: 28152038) -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2019	Variant summary: TTN c.53705T>C (p.Ile17902Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 213576 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.53705T>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 07, 2012	The Ile17902Thr variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 2/8304 E uropean American chromosomes and 2/3916 African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully ass ess the variant's clinical significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2017

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.88
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.4	D;D;.;.;D;D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.026	D;T;.;.;T;T;.
Polyphen		0.88	.;.;.;P;.;.;P
Vest4		0.47
MVP		0.51
MPC		0.24
ClinPred		0.25	T
GERP RS		6.1

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: rs202012910; hg19: chr2-179455043; COSMIC: COSV100597319; COSMIC: COSV100597319;