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

dbSNP: rs104894845

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000157890	SCV000110120	pathogenic	not provided	2013-11-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011516	SCV001361589	pathogenic	Fabry disease	2021-01-12	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 (gnomAD). c.427G>C has been reported in the literature in at least an individual affected with Classic Fabry Disease (example: Eng_1994). These data indicate that the variant is likely to be associated with disease. Enzymatic activity from patient derived samples as well as in vitro studies reveal that the variant resulted in reduced or no enzymatic activity (Altarescu_2001, Lukas_2013). One other ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000011516	SCV002054435	likely pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011516	SCV003445376	pathogenic	Fabry disease	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 143 of the GLA protein (p.Ala143Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 7531540, 17532296, 33437642). ClinVar contains an entry for this variant (Variation ID: 10769). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000011516	SCV000031748	pathogenic	Fabry disease	2002-03-01	no assertion criteria provided	literature only