ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1102G>A (p.Ala368Thr) (rs144994244)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2018-10-30 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.
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 ( /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.

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