ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.427G>C (p.Ala143Pro) (rs104894845)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000157890 SCV000110120 pathogenic not provided 2013-11-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000011516 SCV000205984 likely pathogenic Fabry disease 2014-01-17 criteria provided, single submitter clinical testing The Arg143Pro variant in GLA as been reported in 6 males with Fabry disease, 5 o f whom were of Nova Scotian ancestry (Eng 1994, Branton 2002, Glass 2004). For 2 of them, absence of alpha-galatosidase enzyme activity was reported (Branton 2002). This variant was not identified in large population studies. Computation al analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhe n2, and SIFT) do not provide strong support for or against an impact to the prot ein. Finally, another variant at this position (Arg143Thr) has been reported in multiple individuals with Fabry disease, segregated with disease (Spada 2006, Te rryn 2008), and is considered disease-causing, further supporting that a change at this position is not tolerated. In summary, the presence in multiple affected individuals, absence from large populations, and presence of another variant at the same position all support that this variant is likely to be pathogenic, tho ugh additional studies are required to fully establish its clinical significance .
GeneDx RCV000157890 SCV000207821 pathogenic not provided 2016-04-23 criteria provided, single submitter clinical testing The A143P pathogenic variant has been reported previously in a patient with the classic phenotype of Fabry disease (Eng et al., 1994).
Integrated Genetics/Laboratory Corporation of America RCV000011516 SCV001361589 pathogenic Fabry disease 2019-06-19 criteria provided, single submitter clinical testing Variant summary: GLA c.427G>C (p.Ala143Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183467 control chromosomes. c.427G>C has been reported in the literature in individuals affected with Classic Fabry Disease. These data indicate that the variant is likely to be associated with disease. In vitro enzyme activity studies showed the variant to result in abolished enzyme activity, and patients with this variant have also shown absent enzyme activity (Lukas_2013, Altarescu_2001). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000011516 SCV000031748 pathogenic Fabry disease 2002-03-01 no assertion criteria provided literature only

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