rs200854704
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6
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
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.91621G>A | p.Gly30541Arg | missense_variant | Exon 337 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.91621G>A | p.Gly30541Arg | missense_variant | Exon 337 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 152080Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000845 AC: 21AN: 248412 AF XY: 0.0000890 show subpopulations
GnomAD4 exome AF: 0.000140 AC: 205AN: 1461346Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93AN XY: 726968 show subpopulations
Age Distribution
GnomAD4 genome 0.000105 AC: 16AN: 152080Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74278 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:2
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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). -
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not specified Uncertain:2
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. -
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. -
Distal myopathy Uncertain:1
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Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
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
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Dilated cardiomyopathy 1G Uncertain:1
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
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
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at