rs72648990

Positions:

• chr2-178714130-G-A
• chr2-178714130-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.26528C>T​(p.Thr8843Met) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,613,490 control chromosomes in the GnomAD database, including 2 homozygotes. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T8843K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 6.58

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]

LOC124906100 (HGNC:):

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=0.065653354).
• BP6: Variant 2-178714130-G-A is Benign according to our data. Variant chr2-178714130-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46782.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=5}. Variant chr2-178714130-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.26528C>T	p.Thr8843Met	missense_variant	92/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2562G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.26528C>T	p.Thr8843Met	missense_variant	92/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.503-20374G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000402 AC: 100 AN: 248552 Hom.: 0 AF XY: 0.000378 AC XY: 51 AN XY: 134816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000295

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.000831

GnomAD4 exome AF: 0.000388 AC: 567 AN: 1461286 Hom.: 2 Cov.: 34 AF XY: 0.000393 AC XY: 286 AN XY: 726900

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000376

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74410

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000472

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000856 AC: 7

ExAC AF: 0.000348 AC: 42

EpiCase AF: 0.000764

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TTN: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	This variant is associated with the following publications: (PMID: 24503780, 27066507) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 24, 2021	The TTN c.26528C>T; p.Thr8843Met variant (rs72648990; ClinVar Variation ID: 46782) 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). Given the available evidence, the clinical significance of the p.Thr8843Met variant cannot be determined with certainty. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 28, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Thr7599Met va riant in TTN has been identified by our laboratory in 1 Asian adult with HCM, 1 Ethiopian neonate with congenital HCM, and 2 Caucasian adults with DCM, of which 1 carried a likely pathogenic variant in another gene sufficient to explain the ir disease (Pugh 2014). Additionally, this variant has been identified in 0.1% ( 38/34342) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org/; dbSNP rs72648990) and has been reported in ClinVa r (Variation ID: 46782). Threonine (Thr) at position 7599 is not conserved in ma mmals or evolutionarily distant species, and one mammal (white rhinoceros) carri es a methionine (Met) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools do not provide stro ng support for or against an impact to the protein. In summary, while the clinic al significance of the p.Thr7599Met variant is uncertain, its frequency and lack of conservation suggest that it is more likely to be benign. -

TTN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2017

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.90
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.085	T;.;.;.
Polyphen		0.029	.;.;B;B
Vest4		0.19
MVP		0.30
MPC		0.089
ClinPred		0.047	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: rs72648990; hg19: chr2-179578857; COSMIC: COSV100597464; COSMIC: COSV100597464;