rs753334568

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_001267550.2(TTN):c.95195C>T(p.Pro31732Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P31732P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 10.0

Publications

15 publications found

Variant links:

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 links:

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]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001267550.2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 2-178546041-G-A is Pathogenic according to our data. Variant chr2-178546041-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.95195C>T	p.Pro31732Leu	missense_variant	Exon 343 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.95195C>T	p.Pro31732Leu	missense_variant	Exon 343 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248136

AF XY:

0.00000743

show subpopulations

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111744

Other (OTH)

AF:

0.0000166

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000170

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 14, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with Lambert-Eaton Myasthenic Syndrome (LEMS) who also harbored a pathogenic variant in the CACNA1S gene (Cerino et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies indicates this variant results in an insoluble protein due to improper folding (Hedburg et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22526018, 25500009, 23486992, 23446887, 34839411, 24636144, 35741838, 32039858, 34670883) -

Dec 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 17, 2023

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with hereditary myopathy with early respiratory failure (HMERF). Variable expressivity and reduced penetrance was also reported. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Results were insufficient to demonstrate an effect on protein function related to disease. (PMID: 24636144, 33449170) This variant is also referred to as p.Pro22859Leu or p.Pro30091Leu in published literature. -

Apr 01, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myopathy, myofibrillar, 9, with early respiratory failure

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature truncating codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions or uninformative conservation. (I) 0600 - Variant is located in the annotated C-terminal A-band and the exon has a PSI score of 100% (PMID: 25589632). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic in ClinVar and in over five unrelated individuals with hereditary myopathy with early respiratory failure in homozygous and heterozygous state, including de novo occurrence (PMID:23606733, PMID: 23486992, PMID: 25500009, PMID: 34670883, PMID: 34839411, PMID: 35741838, PMID: 33449170, PMID: 22526018, PMID: 28256728). Heterozygous individuals were reported to have a milder phenotype, subclinical disease or were unaffected, suggesting this variant exhibits variable expressivity and reduced penetrance (PMID:23606733, PMID: 23486992). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies suggest that this variant impacts protein folding (PMID: 24636144, PMID: 33449170). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.95195C>T p.Pro31732Leu in the TTN gene has been reported previously in heterozygous state in individuals affected with Hereditary myopathy with early respiratory failure. Experimental studies have shown that this missense change affects TTN function Algahtani et al., 2019; Hedberg et al., 2014. This variant is located in the A band of TTN. Variants in this region may be relevant for cardiac or neuromuscular disorders Roberts et al., 2015; Ceyhan-Birsoy et al., 2013. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/ Likely pathogenic. The amino acid Pro at position 31732 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence Polyphen, SIFT and MutationTaster predicts conflicting evidence on protein structure and function for this variant. The reference amino acid change at this position on the TTN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Hereditary inclusion-body myopathy

Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM1+PM2+PP1+PP2+PP3 -

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

Pathogenic:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31732 of the TTN protein (p.Pro31732Leu). This variant is present in population databases (rs753334568, gnomAD 0.003%). This missense change has been observed in individual(s) with hereditary myopathy with early respiratory failure (HMERF) (PMID: 22526018, 23486992, 23606733, 25500009). In at least one individual the variant was observed to be de novo. This variant is also known as c.90272C>T (p.Pro30091Leu) and c.68576C>T (p.Pro22859Leu). ClinVar contains an entry for this variant (Variation ID: 132137). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TTN function (PMID: 24636144). This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1G

Pathogenic:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

Pathogenic:1

Aug 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial dilated cardiomyopathy

Pathogenic:1

Jan 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TTN c.87491C>T (p.Pro29164Leu) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248136 control chromosomes (gnomAD). c.87491C>T has been reported in the literature in multiple individuals with characteristic features of hereditary myopathy with early respiratory failure (Palmio_2013, Yue_2014, Hedberg_2014, Cerino_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in impaired protein solubility (Hedberg_2014). The following publications have been ascertained in the context of this evaluation (PMID: 35741838, 24231549, 23606733, 25500009). ClinVar contains an entry for this variant (Variation ID: 132137). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Jul 24, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P22667L variant (also known as c.68000C>T), located in coding exon 170 of the TTN gene, results from a C to T substitution at nucleotide position 68000. The proline at codon 22667 is replaced by leucine, an amino acid with similar properties. This variant (also referred to as p.P31732L and p.P30091L) has been detected in the homozygous and heterozygous states, including a de novo occurrence, in individuals with skeletal muscle and/or respiratory issues consistent with hereditary myopathy with early respiratory failure (HMERF). Homozygous individuals tended to be more severely affected, and not all heterozygous individuals were affected, suggesting this variant exhibits variable expressivity and reduced penetrance (Vasli N et al. Acta Neuropathol., 2012 Aug;124:273-83; Yue D et al. Neuromuscul. Disord., 2015 Feb;25:172-6; Palmio J et al. J Neurol Neurosurg Psychiatry, 2014 Mar;85:345-53; Pfeffer G et al. J. Neurol. Neurosurg. Psychiatry, 2014 Mar;85:331-8; Cerino M et al. Muscle Nerve, 2017 Nov;56:993-997; Savarese M et al. J Neuromuscul Dis, 2020;7:153-166; Rees M et al. Acta Neuropathol, 2021 Mar;141:431-453; Cerino M et al. Genes (Basel), 2022 Jun;13; Liang H et al. Heliyon. 2024 Apr;10(8):e29637). Functional studies suggest this variant may be destabilizing and impact protein folding (Hedberg C et al. Neuromuscul. Disord. 2014 May;24(5):373-9; Rees M et al. Acta Neuropathol, 2021 Mar;141:431-453). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is likely pathogenic for hereditary myopathy with early respiratory failure; however, the association of this alteration with cardiomyopathy is unknown. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;.;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.3

.;.;.;H;.;.;H

PhyloP100

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.5

D;D;.;.;D;D;.

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D;.;.;D;D;.

Polyphen

1.0

.;.;.;D;.;.;D

Vest4

0.58

MutPred

0.79

.;.;.;Loss of disorder (P = 0.085);.;.;Loss of disorder (P = 0.085);

MVP

0.91

MPC

0.47

ClinPred

0.99

GERP RS

5.8

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over