rs869312389
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000169.3(GLA):c.718_719delAA(p.Lys240GlufsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,569 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000169.3 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.718_719delAA | p.Lys240GlufsTer9 | frameshift_variant | Exon 5 of 7 | 1 | NM_000169.3 | ENSP00000218516.4 | ||
RPL36A-HNRNPH2 | ENST00000409170.3 | c.300+3411_300+3412delTT | intron_variant | Intron 4 of 4 | 4 | ENSP00000386655.4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome AF: 9.14e-7 AC: 1AN: 1093569Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 359013
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:5
- -
- -
Variant summary: GLA c.718_719delAA (p.Lys240GlufsX9) 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 (eg. p.Gln250X, p.Arg301X, p.Arg332fsX7). The variant was absent in 178766 control chromosomes. c.718_719delAA has been reported in the literature in multiple individuals affected with Fabry Disease (Blanch_1996, Bono_2011, Germain_2002, Nakano_2013, Shimotori_2007). These data indicate that the variant is very likely to be associated with disease. Enzyme activity assessed in transfected COS-7 cells showed the variant to result in <10% normal enzyme activity, with no response to 1-deoxygalactonojirimycin treatment (Shimotori_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Lys240Glufs*9) 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 individuals with Fabry disease (PMID: 8069316, 18205205, 22551898, 24582695, 27560961). ClinVar contains an entry for this variant (Variation ID: 222371). 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. -
- -
not provided Pathogenic:2
- -
The c.718_719delAA variant has been reported previously in association with Fabry disease using alternative nomenclature (Davies et al., 1994; Sueoka et al., 2015). The c.718_719delAA variant is not observed in large population cohorts (Lek et al., 2016). The deletion causes a frameshift starting with codon Lysine 240, changes this amino acid to a Glutamic Acid residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Lys240GlufsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.718_719delAA as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at