chr2-178529076-C-G
Variant summary
Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001267550.2(TTN):āc.106675G>Cā(p.Glu35559Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,613,336 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. 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: Benign. The variant received -13 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.106675G>C | p.Glu35559Gln | missense_variant | Exon 360 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.106675G>C | p.Glu35559Gln | missense_variant | Exon 360 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.000296 AC: 45AN: 152132Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000426 AC: 106AN: 248704 AF XY: 0.000504 show subpopulations
GnomAD4 exome AF: 0.000379 AC: 554AN: 1461086Hom.: 3 Cov.: 32 AF XY: 0.000405 AC XY: 294AN XY: 726800 show subpopulations
Age Distribution
GnomAD4 genome 0.000296 AC: 45AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22AN XY: 74412 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
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This variant is associated with the following publications: (PMID: 27930701, 23861362, 28440294) -
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TTN: BP4 -
not specified Uncertain:1Benign:3
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Variant classified as Uncertain Significance - Favor Benign. The p.Glu32991Gln v ariant has been identified by our laboratory in 1 Caucasian individual with idio pathic cardiomyopathy and in 0.1% (34/30728) of South Asian chromosomes by the G enome Aggreagation Database (gnomAD, http://gnomad.broadinstitute.org/, dbSNP rs 199632397). This variant was also identified in a 23-year-old female who died su ddenly; however, the specific cause of her death was unexplained even after auto psy (Sanchez 2016). This variant has also been reported in ClinVar (Variation ID 192135). Computational prediction tools and conservation analysis suggest that the p.Glu32991Gln variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Glu32991Gln variant is uncertain, its frequency suggests that it is more likely to be benign. -
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Cardiovascular phenotype Uncertain:1Benign: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. -
There is insufficient or conflicting evidence for classification of this alteration. -
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. -
TTN-related disorder Uncertain:1
The TTN c.106675G>C variant is predicted to result in the amino acid substitution p.Glu35559Gln. This variant, along with two additional TTN variants, was reported in one case of sudden death, however no additional studies were performed to help assess the pathogenicity of this variant (described as c.98971G>C (p.Glu32991Gln) with an alternate transcript NM_133378, Sanchez et al. 2016. PubMed ID: 27930701). This variant is reported in 0.11% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179393803-C-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
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. -
TTN-related myopathy Uncertain:1
The TTN c.106675G>C (p.Glu35559Gln) variant is a missense variant. The p.Glu35559Gln variant has been reported in one publication in which it is described as c.98971G>C (p.Glu32991Gln). The variant was identified in a heterozygous state in a 23 year-old female with sudden unexplained death. The p.Glu35559Gln variant has not been reported in association with autosomal dominant or recessive TTN-related myopathies. The p.Glu35559Gln variant is reported at a frequency of 0.001146 in the South Asian population of the Genome Aggregation Database. Although this frequency is too high to suggest an association with dominant TTN-related phenotypes, it is consistent with a potential association with autosomal recessive phenotypes. This variant is located within the M band of the protein. In silico prediction of pathogenicity for this variant are mixed, but lean towards benign. However, currently available in silico prediction tools may have limited utility in the assessment of missense variants in the TTN gene (Rees et al. 2021). Based on the limited evidence and application of the ACMG criteria, the p.Glu35559Gln variant is classified as a variant of uncertain significance for TTN-related myopathy. -
Cardiomyopathy Benign:1
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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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at