rs370890454

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The NM_001267550.2(TTN):​c.69338G>A​(p.Arg23113Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,613,314 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 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

6
5
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 7.86
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 Uncertain_significance. Variant got 0 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=0.3271515).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.69338G>A p.Arg23113Gln missense_variant 324/363 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.69338G>A p.Arg23113Gln missense_variant 324/3635 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.000235
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000927
AC:
23
AN:
248036
Hom.:
0
AF XY:
0.0000743
AC XY:
10
AN XY:
134530
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000197
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.000238
AC:
348
AN:
1461280
Hom.:
0
Cov.:
35
AF XY:
0.000206
AC XY:
150
AN XY:
726918
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000281
Gnomad4 OTH exome
AF:
0.000514
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152034
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
AN XY:
74220
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000213
Hom.:
0
Bravo
AF:
0.000200
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000122
AC:
1
ExAC
AF:
0.0000497
AC:
6
EpiCase
AF:
0.000382
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicAug 15, 2024PM2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxJun 05, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityApr 16, 2019- -
not specified Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJul 21, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 30, 2015The p.Arg20545Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/66666 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s370890454). Computational prediction tools and conservation analysis suggest th at the p.Arg20545Gln variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Arg20545Gln variant is uncertain. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 11, 2021Variant summary: TTN c.61634G>A (p.Arg20545Gln) results in a 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 248036 control chromosomes, predominantly at a frequency of 0.0002 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.0002 vs 0.00039), allowing no conclusion about variant significance. c.61634G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Haas_2015, Mazzarotto_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=1) and uncertain significance (n=4). 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 10, 2017- -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 06, 2016- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 25, 2013The p.R20545Q variant (also known as c.61634G>A) is located in coding exon 272 of the TTN gene. This alteration results from a G to A substitution at nucleotide position 61634. The arginine at codon 20545 is replaced by glutamine, an amino acid with highly similar properties. This variant was observed in a 4-year old male diagnosed with methylmalonic acidemia and hyperhomocysteinemia in transwith another variant. The variant was found in whole exome analysis. This child did not show any symptoms of cardiomyopathy, but given the young age this diagnosis cannot be ruled out (Yu et al.Am. J. Hum. Genet. 2013 Sep;93(3):506-14).Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.01% (1/12050). This variant was not observed in 3824 of African American alleles, but observed in 0.01% (1/8226) of European American alleles studied. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP) and 1000 Genomes Project. This amino acid position is highly conserved on sequence alignment. This variant is predicted to be probably damaging by PolyPhen in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.R20545Q remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.078
T
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
24
DANN
Benign
0.96
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;.;D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.33
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.19
D
MutationAssessor
Pathogenic
3.5
.;.;.;H;.;.;H
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.1
D;D;.;.;D;D;.
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
D;D;.;.;D;D;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
0.48
MVP
0.43
MPC
0.50
ClinPred
0.55
D
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs370890454; hg19: chr2-179441724; COSMIC: COSV60157059; COSMIC: COSV60157059; API