chrX-101398919-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000169.3(GLA):c.667T>C(p.Cys223Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C223Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.667T>C | p.Cys223Arg | missense_variant | 5/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+3462A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.667T>C | p.Cys223Arg | missense_variant | 5/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jan 20, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2016 | The p.C223R variant (also known as c.667T>C), located in coding exon 5 of the GLA gene, results from a T to C substitution at nucleotide position 667. The cysteine at codon 223 is replaced by arginine, an amino acid with highly dissimilar properties. One study of families with Fabry disease reported this variant in a female individual considered an obligate carrier due to family history of a father affected with classic disease, though clinical details were limited (Shabbeer J et al. Mol Genet Metab. 2002;76(1):23-30; Shabbeer J et al. Hum Mutat. 2005;25(3):299-305). In addition, other alterations affecting the same amino acid (p.C223G (c.667T>G) and p.C223Y (c.668G>A)) have also been reported in association with Fabry disease (Germain DP et al. Biochem Biophys Res Commun. 1999;257(3):708-13; Shabbeer J et al. Mol Genet Metab. 2002;76(1):23-30). Furthermore, structural analyses indicate this variant destabilizes a known disulfide bond, likely resulting in significant destabilization of folding in the region (Garman SC et al. J Mol Biol. 2004;337(2):319-35; Saito S et al. PLoS ONE. 2013;8(12):e84267). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at