rs200854704
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6
The NM_001267550.2(TTN):c.91621G>A(p.Gly30541Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000137 in 1,613,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
TTN
NM_001267550.2 missense
NM_001267550.2 missense
Scores
6
6
4
Clinical Significance
Conservation
PhyloP100: 6.11
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, TTN
BP6
?
Variant 2-178550217-C-T is Benign according to our data. Variant chr2-178550217-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47513.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7, Benign=2}. Variant chr2-178550217-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.91621G>A | p.Gly30541Arg | missense_variant | 337/363 | ENST00000589042.5 | |
| TTN-AS1 | NR_038272.1 | n.2043+7856C>T | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.91621G>A | p.Gly30541Arg | missense_variant | 337/363 | 5 | NM_001267550.2 | P1 | |
| ENST00000603415.1 | n.1334C>T | non_coding_transcript_exon_variant | 1/1 | ||||||
| TTN-AS1 | ENST00000659121.1 | n.416+26581C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152080Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000845 AC: 21AN: 248412Hom.: 0 AF XY: 0.0000890 AC XY: 12AN XY: 134760
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:2
| Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 10, 2017 | p.Gly27973Arg) (c.83917G>A) in exon 286 of the TTN gene (NM_133378.4; Chr2:179414944C>T; GrCh37) Given that this variant has been seen in 2 individuals who both had other pathogenic variants identified on their tests at the testing lab, and its prevalence in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated cases of cardiomyopathy (not including this patient's family). There is no case data in the literature available for review. This variant is reported in ClinVar. It is classified as a variant of uncertain significance by two other labs (Invitae and Illumina Clinical Services Laboratory), and likely benign by the NIH. LMM has seen this variant in 2 individuals: 1 Caucasian adult with HCM and 1 Asian infant with DCM, both of whom had an additional pathogenic variant sufficient to cause their disease. Per the test report, "computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein." This variant is almost conserved across more than 100 species, as are neighboring amino acids. The variant was reported online in 23 of 138,133 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 4 of 12,000 individuals of African descent (highest MAF=0.016%), 2 of 9,408 individuals of East Asian descent, 13 of 62,988 individuals of European descent, 2 of 15,387 individuals of South Asian descent, 1 of 17,202 individuals of Latino descent and 1 of 3,218 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Data suggests that a minor allele frequency below 0.004% is an appropriate threshold for considering a variant's pathogenicity in HCM given the rarity of the disease and its heterogeneity (Whiffen et al 2016). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 20, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2020 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 20, 2017 | Variant classified as Uncertain Significance - Favor Benign. The p.Gly27973Arg v ariant in TTN has been identified by our laboratory in 1 Caucasian adult with HC M and 1 Asian infant with DCM, both of whom carried an additional pathogenic var iant sufficient to cause their disease. It has also been identified in 23/276266 pan ethnic chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs200854704). Computational prediction tools and con servation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Gly27973Arg varia nt is uncertain, these data suggest that it is more likely to be benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 25, 2019 | Variant summary: TTN c.83917G>A (p.Gly27973Arg) results in a non-conservative amino acid change located in the A-band region (cardiodb.org) 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 8.5e-05 in 248412 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (8.5e-05 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.83917G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported in the literature. Four ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. However, one ClinVar entry reports the variant to occur in two independent individuals, one affected with HCM and another with DCM, whom both carried another pathogenic variant. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2017 | - - |
Dilated cardiomyopathy 1G Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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 submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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. - |
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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. - |
Tibial muscular dystrophy Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;.;D;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;D;D;.
Polyphen
1.0
.;.;.;D;.;.;D
Vest4
MutPred
0.84
.;.;.;Gain of MoRF binding (P = 0.0158);.;.;Gain of MoRF binding (P = 0.0158);
MVP
MPC
0.51
ClinPred
T
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at