rs200001206

chr2-178597958-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.57212T>C(p.Ile19071Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000395 in 1,613,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:6
• Conservation: PhyloP100: 5.96

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=0.089241415).
• BP6: Variant 2-178597958-A-G is Benign according to our data. Variant chr2-178597958-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47118.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=2}. Variant chr2-178597958-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.57212T>C	p.Ile19071Thr	missense_variant	293/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.3450+277A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.57212T>C	p.Ile19071Thr	missense_variant	293/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+277A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

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: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000318 AC: 79 AN: 248686 Hom.: 0 AF XY: 0.000289 AC XY: 39 AN XY: 134934

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000789

Gnomad NFE exome AF: 0.000515

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000400 AC: 585 AN: 1461194 Hom.: 0 Cov.: 33 AF XY: 0.000378 AC XY: 275 AN XY: 726868

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000936

Gnomad4 NFE exome AF: 0.000467

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74426

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000478 Hom.: 0

Bravo AF: 0.000268

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000265 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000215 AC: 26

EpiCase AF: 0.000873

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 29, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2022	The TTN c.57212T>C; p.Ile19071Thr variant (rs200001206; ClinVar Variation ID:47118) 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.Ile19071Thr variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 31, 2012	The Ile16503Thr variant in TTN has been identified in 1/3071 African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). This frequency is insufficient to rule out pathogeni city as this may have been a presymptomatic individual. Isoleucine (Ile) at posi tion 16503 is not well conserved in evolution, suggesting that a change may be t olerated though this is not predictive enough to rule out pathogenicity. Other computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein . Additional information is needed to fully assess the clinical significance of the Ile16503Thr variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 06, 2020	Variant summary: TTN c.49508T>C (p.Ile16503Thr) results in a non-conservative amino acid change located in the A-band region (cardiodb.org) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 248686 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00032 vs 0.00063), allowing no conclusion about variant significance. c.49508T>C has been reported in the literature in at least one patient evaluated for sudden cardiac death (Hertz_2016). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function have been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2017

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2019

The p.I10006T variant (also known as c.30017T>C), located in coding exon 120 of the TTN gene, results from a T to C substitution at nucleotide position 30017. The isoleucine at codon 10006 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Benign	0.92
Eigen	Benign	0.0064
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.089	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.98	N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;D;.;.;D;D;.
REVEL	Benign	0.12
Sift	Benign	0.071	T;T;.;.;T;T;.
Polyphen		0.062	.;.;.;B;.;.;B
Vest4		0.34
MVP		0.50
MPC		0.12
ClinPred		0.056	T
GERP RS		5.9

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: rs200001206; hg19: chr2-179462685;