rs200716930
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM5PP2BP4_Moderate
The NM_001267550.2(TTN):c.103909C>T(p.Arg34637Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R34637Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.103909C>T | p.Arg34637Trp | missense_variant | 358/363 | ENST00000589042.5 | NP_001254479.2 | |
TTN-AS1 | NR_038272.1 | n.220-3026G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.103909C>T | p.Arg34637Trp | missense_variant | 358/363 | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.416+9070G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000442 AC: 11AN: 248988Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135084
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461652Hom.: 0 Cov.: 40 AF XY: 0.0000124 AC XY: 9AN XY: 727110
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 24, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 18, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 01, 2015 | The p.Arg32069Trp variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/11534 of Latino chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200716930). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Arg32069Trp variant is uncertain. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 03, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 34637 of the TTN protein (p.Arg34637Trp). This variant is present in population databases (rs200716930, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 203074). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at