ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.1102G>A (p.Ala368Thr) (rs144994244)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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.
Invitae RCV000463728 SCV000543777 uncertain significance Fabry disease 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 368 of the GLA protein (p.Ala368Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs144994244, ExAC 0.1%). This variant has been reported in a female with suspected Fabry disease, in a hemizygous male with this condition and in an individual with dilated cardiomyopathy (PMID: 23935525, 27576502, 24503780). ClinVar contains an entry for this variant (Variation ID: 42451). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000463728 SCV001360072 uncertain significance Fabry disease 2018-12-05 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001507537 SCV001713142 uncertain significance not provided 2019-07-08 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000463728 SCV001422795 likely benign Fabry disease 2020-01-22 no assertion criteria provided 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).

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