rs104894841
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000169.3(GLA):c.679C>T(p.Arg227Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,205,421 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R227R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000169.3 stop_gained
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.679C>T | p.Arg227Ter | stop_gained | 5/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+3450G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.679C>T | p.Arg227Ter | stop_gained | 5/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000893 AC: 1AN: 111978Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34166
GnomAD4 exome AF: 9.15e-7 AC: 1AN: 1093443Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 358995
GnomAD4 genome ? AF: 0.00000893 AC: 1AN: 111978Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34166
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:6
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Arg227*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fabry disease and hypertrophic cardiomyopathy (PMID: 8395937, 18205205, 25439755, 26047621). ClinVar contains an entry for this variant (Variation ID: 10733). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 21, 2020 | Variant summary: GLA c.679C>T (p.Arg227X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 183590 control chromosomes (gnomAD and publication data). c.679C>T has been reported in the literature in multiple individuals affected with Fabry Disease (Ashley_2001, Davies_1993, Germain_2002, Gomez_2012, Nakano_2013, Giugliani_2013). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Jan 30, 2014 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 08, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate this variant reduced GLA activity to 2% of controls (Shimotori et al., 2008); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25974833, 18205205, 25439755, 23935525, 25525159, 26047621, 28728877, 31542871, 8395937, 30477121, 31411008, 33072517, 33204599, 33673806) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 10, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at