Submissions for variant NM_000169.3(GLA):c.1102G>A (p.Ala368Thr)

dbSNP: rs144994244

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035300	SCV000058948	uncertain significance	not specified	2012-07-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ala368Thr varia nt in GLA has been identified in 2/3835 African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS). Alanine (Ala) at position 368 is not conserved in mammals with other spec ies carrying various other amino acid residues and 1 species (atlantic salmon) c arries a threonine (Thr; this variant), suggesting that this change may be toler ated. In addition, computational analyses (biochemical amino acid properties, Al ignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. In summary, the frequency of this variant and lack of amino acid conservation su ggests that it may be more likely benign, but additional information is needed t o fully assess its clinical significance.
GeneDx	RCV000035300	SCV000513155	likely benign	not specified	2015-04-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463728	SCV000543777	likely benign	Fabry disease	2025-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000463728	SCV001360072	uncertain significance	Fabry disease	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 368 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An in-vitro functional assay using transfected HEK-293 cells has shown that this variant causes a small decrease in alpha-galactosidase activity (PMID: 31996269). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780), in a female suspected to be affected with Fabry disease (PMID: 23935525), in a male undergoing hemodialysis (PMID: 27576502), and in an unaffected female (PMID: 32418857). This variant has been identified in 19/205199 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000463728	SCV001422795	likely benign	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Ala368Thr variant in GLA has been reported in 1 African American female with Fabry Disease (PMID: 24503780), and has been identified in 0.1% (19/18974) of African chromosomes, including 8 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144994244). This variant has also been reported in ClinVar as a VUS by Invitae and the Laboratory for Molecular Medicine (Partners Healthcare) and likely benign by GeneDx (Variation ID:42451). In vitro functional studies provide some evidence that the p.Ala368Thr variant may not impact protein function (PMID: 23935525, 24334114, 27576502). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One affected individual with this variant has an alternative molecular basis for Fabry disease, suggesting this variant may not cause the disease (PMID: 24503780). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BS3_supporting, BP5 (Richards 2015).
Mayo Clinic Laboratories, Mayo Clinic	RCV001507537	SCV001713142	uncertain significance	not provided	2019-07-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000463728	SCV002054471	likely benign	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035300	SCV002500542	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: GLA c.1102G>A (p.Ala368Thr) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 1208524 control chromosomes, including 15 hemizygotes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GLA causing Fabry Disease (4.9e-05 vs 0.005), allowing no conclusion about variant significance. c.1102G>A has been reported in the literature in male and female individuals suspected or affected with Fabry Disease (e.g. Turaca_2012, Lukas_2013, Pereira_2014, Silva_2016, Stiles_2020, Varela_2020) and an individual affected with dilated cardiomyopathy (Pugh_2014). One of the reported male patients was a 73-year-old undergoing hemodialysis for approximately 5 years who denied experiencing classical FD symptoms; clinical manifestations of the patient included: Cornea verticillata, Fabry nephropathy and Left ventricular hypertrophy (Silva_2016). These reports do not provide unequivocal conclusions about association of the variant with Fabry Disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal enzyme activity (e.g. Lukas_2013, Benjamin_2017, Oommen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27657681, 29330335, 37441486, 23935525, 30985853, 31036492, 24334114, 24503780, 27576502, 32418857, 22551898, 31996269). ClinVar contains an entry for this variant (Variation ID: 42451). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002426548	SCV002740601	likely benign	Cardiovascular phenotype	2023-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.