rs72647870

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001267550.2(TTN):ā€‹c.3409G>Cā€‹(p.Gly1137Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,613,956 control chromosomes in the GnomAD database, including 10 homozygotes. 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: š‘“ 0.0023 ( 1 hom., cov: 33)
Exomes š‘“: 0.0031 ( 9 hom. )

Consequence

TTN
NM_001267550.2 missense

Scores

6
7
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 7.87
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 Benign. Variant got -12 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=0.017946422).
BP6
Variant 2-178781235-C-G is Benign according to our data. Variant chr2-178781235-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46949.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=6, Uncertain_significance=1}. Variant chr2-178781235-C-G is described in Lovd as [Likely_benign]. Variant chr2-178781235-C-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00229 (349/152254) while in subpopulation NFE AF= 0.00385 (262/68018). AF 95% confidence interval is 0.00347. There are 1 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TTNNM_001267550.2 linkuse as main transcriptc.3409G>C p.Gly1137Arg missense_variant 21/363 ENST00000589042.5 NP_001254479.2
TTNNM_133379.5 linkuse as main transcriptc.3409G>C p.Gly1137Arg missense_variant 21/46 ENST00000360870.10 NP_596870.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.3409G>C p.Gly1137Arg missense_variant 21/3635 NM_001267550.2 ENSP00000467141 P1
TTNENST00000360870.10 linkuse as main transcriptc.3409G>C p.Gly1137Arg missense_variant 21/465 NM_133379.5 ENSP00000354117 Q8WZ42-6

Frequencies

GnomAD3 genomes
AF:
0.00229
AC:
349
AN:
152136
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00387
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00385
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00215
AC:
541
AN:
251114
Hom.:
0
AF XY:
0.00204
AC XY:
277
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000665
Gnomad ASJ exome
AF:
0.00179
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00407
Gnomad NFE exome
AF:
0.00347
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00309
AC:
4520
AN:
1461702
Hom.:
9
Cov.:
31
AF XY:
0.00307
AC XY:
2229
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.000671
Gnomad4 ASJ exome
AF:
0.00168
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00416
Gnomad4 NFE exome
AF:
0.00362
Gnomad4 OTH exome
AF:
0.00296
GnomAD4 genome
AF:
0.00229
AC:
349
AN:
152254
Hom.:
1
Cov.:
33
AF XY:
0.00220
AC XY:
164
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.000981
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00387
Gnomad4 NFE
AF:
0.00385
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00313
Hom.:
1
Bravo
AF:
0.00191
TwinsUK
AF:
0.00297
AC:
11
ALSPAC
AF:
0.00259
AC:
10
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00430
AC:
37
ExAC
AF:
0.00211
AC:
256
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00316
EpiControl
AF:
0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:15
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 05, 2021Variant summary: TTN c.3409G>C (p.Gly1137Arg) results in a non-conservative amino acid change located in the near Z-disk region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 395852 control chromosomes in the gnomAD database (v2.1 and v3.1 datasets), including 1 homozygote. The observed variant frequency is approximately 5.75 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is benign. c.3409G>C has been reported in the literature in individuals affected with individuals affected with hypertrophic cardiomyopathy and sudden unexplained death, however in at least one of these patients co-occurring potentially pathogenic variant(s) could explain the phenotype (Lopes_2013, Campuzano_2015). These reports do not support the association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (1x), likely benign (6x) / benign (1x). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 13, 2017This 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. -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 30, 2014p.Gly1137Arg in exon 21 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (230/67514) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs72647870). -
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 11, 2015- -
not provided Benign:2
Likely benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024TTN: BS2 -
Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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- -
Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioAug 30, 2019- -
Tibial muscular dystrophy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoJul 06, 2017- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 07, 2019Other strong data supporting benign classification -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D;D;.;D;D;D;D
M_CAP
Benign
0.073
D
MetaRNN
Benign
0.018
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.015
D
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-5.8
D;D;.;.;D;D;.;D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0030
D;D;.;.;D;D;.;D
Sift4G
Pathogenic
0.0010
.;.;.;.;.;.;.;D
Polyphen
1.0
.;.;.;D;.;.;D;D
Vest4
0.53
MVP
0.73
MPC
0.51
ClinPred
0.060
T
GERP RS
5.9

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: rs72647870; hg19: chr2-179645962; COSMIC: COSV104641231; COSMIC: COSV104641231; API