chr2-178799566-G-A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_001267550.2(TTN):c.835C>T(p.Arg279Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000397 in 1,614,026 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.835C>T | p.Arg279Trp | missense_variant | Exon 6 of 363 | ENST00000589042.5 | NP_001254479.2 | |
TTN | NM_133379.5 | c.835C>T | p.Arg279Trp | missense_variant | Exon 6 of 46 | ENST00000360870.10 | NP_596870.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.835C>T | p.Arg279Trp | missense_variant | Exon 6 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 | ||
TTN | ENST00000360870.10 | c.835C>T | p.Arg279Trp | missense_variant | Exon 6 of 46 | 5 | NM_133379.5 | ENSP00000354117.4 |
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000187 AC: 47AN: 251394Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135872
GnomAD4 exome AF: 0.000409 AC: 598AN: 1461850Hom.: 1 Cov.: 31 AF XY: 0.000375 AC XY: 273AN XY: 727224
GnomAD4 genome AF: 0.000276 AC: 42AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:9Other:1
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Myopathy, myofibrillar, 9, with early respiratory failure Pathogenic:1Uncertain:1
This 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not specified Benign:2
Variant summary: TTN c.835C>T (p.Arg279Trp) results in a non-conservative amino acid change located in the 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 0.00019 in 282792 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.835C>T has been reported in the literature in multiple individuals affected with TTN-related conditions without strong evidence for causality (e.g., Lange_2005, Campuzan_2015, Sanchez_2016, van Spaendonck-Zwart_2014). At-least two co-occurrences with other pathogenic variant(s) have been reported in cis with this variant (TTN c.87491C>T, p.Pro29164Leu, Lange_2005; c.69086_69095del10, p.Arg23029ThrfsX9, van Spaendonck-Zwart_2014), providing supporting evidence for a benign role. Two publications report experimental evidence evaluating an impact on protein function, demonstrating reduced binding to nbd1 in mutant cells (Lange_2005, Chaveau_2014). However, neither study provides quantitative data indicating the strength of the effect. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 24105469, 24569025, 24578547, 27930701, 20708934, 24558114, 15802564, 24271327, 24231549). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as a variant of uncertain significance, and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
proposed classification - variant undergoing re-assessment, contact laboratory -
Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
This 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;C1858763:Dilated cardiomyopathy 1G Uncertain:1
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Dilated cardiomyopathy 1G Uncertain:1
This 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. -
Early-onset myopathy with fatal cardiomyopathy Uncertain:1
This 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. -
Tibial muscular dystrophy Uncertain:1
This 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. -
Cardiovascular phenotype Uncertain:1
The p.R279W variant (also known as c.835C>T), located in coding exon 5 of the TTN gene, results from a C to T substitution at nucleotide position 835. The arginine at codon 279 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in cis with a truncating TTN alteration in a family with both dilated cardiomyopathy and peripartum cardiomyopathy (van Spaendonck-Zwarts KY et al. Eur Heart J. 2014;35:2165-73). This alteration has also been reported as a secondary cardiac variant in an exome cohort, and was detected in a sudden unexplained death case with variants in other cardiac-related genes (Ng D et al. Circ Cardiovasc Genet. 2013;6:337-46; Sanchez O et al. PLoS ONE. 2016;11(12):e0167358). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Cardiomyopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at