ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.680G>A (p.Arg227Gln) (rs104894840)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000157898 SCV000110134 pathogenic not provided 2016-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000157898 SCV000207829 pathogenic not provided 2018-06-05 criteria provided, single submitter clinical testing The R227Q missense variant in the GLA gene has been reported multiple times in association with the classic phenotype of Fabry disease (Eng et al., 1993; Lukas et al., 2013). In 148 unrelated families affected with Fabry disease, R227Q was found on 2% of GLA alleles (Eng et al., 1993). Functional studies in HEK-293 cells found that R227Q is associated with 0% residual enzyme activity compared to wild-type (Wu et al., 2011; Lukas et al., 2013). The R227Q variant is not observed in large population cohorts (Lek et al., 2016). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, R227Q is interpreted as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000011478 SCV000695744 pathogenic Fabry disease 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The GLA c.680G>A (p.Arg227Gln) variant is indicated to be a CpG mutational hot spot, causing a missene change involving a conserved nucleotide that 4/5 in silico tools predict a damaging outcome. The variant of interest has not been observed in controls (ExAC, 1000 Gs, ESP, or publication controls) and has been reported in multiple affected individuals including a very large Fabry Disease family, which the variant segregates with disease. In addition, affected individuals were observed to have a significant reduction in enzyme activity, along with multiple clinical diagnostic laboratories and databases citing the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000011478 SCV000834471 pathogenic Fabry disease 2018-04-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 227 of the GLA protein (p.Arg227Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in multiple unrelated individuals and families affected with Fabry disease (PMID:7504405, 26652600, 17206462, 10916280, 15713906). ClinVar contains an entry for this variant (Variation ID: 10732). Experimental studies have shown that this missense change causes a drastic reduction in GLA enzymatic activity in vitro (PMID: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000011478 SCV000967592 pathogenic Fabry disease 2018-07-18 criteria provided, single submitter clinical testing The p.Arg227Gln variant in GLA (ClinVar variation ID: 10732) has been reported i n at least 6 individuals with Fabry disease, segregated with disease in approxim ately 30 affected relatives from 3 families (including 17 manifesting females) ( Eng 1993, Morrone 2003, Marier 2010, Fancellu 2015). This variant and was absent from large population studies. Functional studies provide some evidence that th e p.Arg227Gln variant showed decreased alpha-Gal activity, consistent with class ic Fabry disease (Wu 2011, Lukas 2013). Computational prediction tools and conse rvation analysis suggest that the p.Arg227Gln variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Fabry d isease in an X-linked manner based upon proband counts, segregation studies, abs ence from controls, and functional evidence. ACMG/AMP Criteria applied: PP1_Stro ng, PS3_Moderate, PS4_Moderate, PM2, PP3.
OMIM RCV000011478 SCV000031710 pathogenic Fabry disease 1993-12-01 no assertion criteria provided literature only

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