rs201523784

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_001267550.2(TTN):​c.25619C>T​(p.Ser8540Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,613,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.00043 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00062 ( 1 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

5
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:9

Conservation

PhyloP100: 1.12
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TTN. . Gene score misZ -1.1021 (greater than the threshold 3.09). Trascript score misZ 6.9794 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, tibial muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 9, TTN-related myopathy, dilated cardiomyopathy 1G, arrhythmogenic right ventricular cardiomyopathy, myopathy, myofibrillar, 9, with early respiratory failure, familial isolated dilated cardiomyopathy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, autosomal recessive limb-girdle muscular dystrophy type 2J.
BP4
Computational evidence support a benign effect (MetaRNN=0.015490621).
BP6
Variant 2-178717115-G-A is Benign according to our data. Variant chr2-178717115-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46762.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5, Benign=4}. Variant chr2-178717115-G-A is described in Lovd as [Benign]. Variant chr2-178717115-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.25619C>T p.Ser8540Phe missense_variant 88/363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.25619C>T p.Ser8540Phe missense_variant 88/3635 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000573
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000576
AC:
143
AN:
248154
Hom.:
0
AF XY:
0.000505
AC XY:
68
AN XY:
134624
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.000493
Gnomad ASJ exome
AF:
0.00389
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000262
Gnomad FIN exome
AF:
0.0000467
Gnomad NFE exome
AF:
0.000650
Gnomad OTH exome
AF:
0.000499
GnomAD4 exome
AF:
0.000622
AC:
908
AN:
1460766
Hom.:
1
Cov.:
31
AF XY:
0.000579
AC XY:
421
AN XY:
726616
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000470
Gnomad4 ASJ exome
AF:
0.00406
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000163
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.000639
Gnomad4 OTH exome
AF:
0.000812
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152290
Hom.:
0
Cov.:
33
AF XY:
0.000322
AC XY:
24
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000573
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000775
Hom.:
1
Bravo
AF:
0.000468
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000605
AC:
5
ExAC
AF:
0.000505
AC:
61
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000546
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 02, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 14, 2015Variant classified as Uncertain Significance - Favor Benign. The p.Ser7296Phe va riant in TTN has been identified by our laboratory in 1 infant with unspecified cardiomyopathy, 1 Ashkenazi Jewish adult with HCM, and in 1 Caucasian adult with DCM who also carried a likely pathogenic variant in TTN. In addition, this vari ant has been identified in 54/66002 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201523784). Serine ( Ser) at position 7296 is not conserved in mammals or evolutionarily distant spec ies and 4 species (hedgehog, tenrec, Southern platyfish and zebrafish) carry a p henylalanine (Phe) at this position, raising the possibility that this change ma y be tolerated. Additional computational tools do not provide strong support for or against and impact to the protein. In summary, while the clinical significan ce of the p.Ser7296Phe variant is uncertain, its frequency and the presence of t he variant amino acid in other species suggest that it is more likely to be beni gn. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 20, 2021Variant summary: TTN c.21887C>T (p.Ser7296Phe) results in a non-conservative amino acid change located in the I-band 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 0.00058 in 248154 control chromosomes, predominantly at a frequency of 0.00065 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.21887C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (ALMS1 c.11629C>T, p.Gln3877X; MYH7 c.2539A>G , p.Lys847Glu), providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign/benign n=5, VUS n=2). Based on the evidence outlined above, the variant was classified as benign. -
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2022TTN: PM2, BP4 -
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 06, 2021This variant is associated with the following publications: (PMID: 23861362, 27841875) -
Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 09, 2021- -
Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterresearchAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteJan 25, 2017This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
19
DANN
Benign
0.96
Eigen
Benign
-0.083
Eigen_PC
Benign
-0.0063
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.86
D;T;.;T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.015
T;T;T;T
MetaSVM
Benign
-0.66
T
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-3.6
D;.;.;.
REVEL
Uncertain
0.34
Sift
Uncertain
0.0030
D;.;.;.
Polyphen
0.0
.;.;B;B
Vest4
0.31
MVP
0.50
MPC
0.092
ClinPred
0.028
T
GERP RS
2.5

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201523784; hg19: chr2-179581842; COSMIC: COSV59928504; COSMIC: COSV59928504; API