rs201614524
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_001267550.2(TTN):c.64903C>T(p.Arg21635Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,344 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21635H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.64903C>T | p.Arg21635Cys | missense_variant | 310/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2933G>A | non_coding_transcript_exon_variant | 11/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.64903C>T | p.Arg21635Cys | missense_variant | 310/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-12858G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152046Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000604 AC: 15AN: 248496Hom.: 1 AF XY: 0.0000519 AC XY: 7AN XY: 134802
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461298Hom.: 1 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726920
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74228
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 20, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 25, 2019 | This variant is associated with the following publications: (PMID: 24503780) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TTN p.Arg19994Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs201614524) and ClinVar (classified as likely benign by GeneDx and uncertain significance by Laboratory for Molecular Medicine). The variant was identified in control databases in 17 of 279872 chromosomes (1 homozygous) at a frequency of 0.00006074 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 5 of 19474 chromosomes (freq: 0.000257), European (non-Finnish) in 10 of 127774 chromosomes (freq: 0.000078), African in 1 of 24194 chromosomes (freq: 0.000041) and Latino in 1 of 35352 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Arg19994 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 13, 2023 | Variant summary: TTN c.57199C>T (p.Arg19067Cys) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 248496 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6e-05 vs 0.00039), allowing no conclusion about variant significance. c.57199C>T has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Pugh_2014) without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 24503780). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 08, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Arg19067Cys var iant in TTN has been identified in 2/8240 European American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/). This variant was also identified in one individual with DCM who had t wo other variants, including a TTN variant inherited in cis with this variant. F amily studies suggest that the TTN variants may be less likely disease causing b ut computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) suggest that the Arg19067Cys variant may impact the protein (please note: the accuracy of these tools is unknown and this informatio n is not predictive enough to determine pathogenicity). Additional information i s needed to fully assess the clinical significance of the Arg19067Cys variant. - |
Myopathy, myofibrillar, 9, with early respiratory failure Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 24, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at