ClinVar Miner

Submissions for variant NM_139058.3(ARX):c.187G>A (p.Ala63Thr) (rs769996976)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000705004 SCV000833981 uncertain significance Epileptic encephalopathy, early infantile, 1; Mental retardation, with or without seizures, ARX-related, X-linked 2018-01-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 63 of the ARX protein (p.Ala63Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs769996976, ExAC 0.03%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals with ARX-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics RCV000764874 SCV000896030 uncertain significance Epileptic encephalopathy, early infantile, 1; Mental retardation, with or without seizures, ARX-related, X-linked; Corpus callosum agenesis-abnormal genitalia syndrome; Lissencephaly 2, X-linked; Partington syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779753 SCV000916528 uncertain significance not specified 2017-11-07 criteria provided, single submitter clinical testing Variant Summary: The ARX c.187G>A (p.Ala63Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured here due to low reliability index) predict a "benign" outcome. However, these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 0.00003175 (2/62990), predominantly observed in the Latino population at a frequency of 0.0002661(2/7517, including 1 hemizygote). This frequency does not exceed the estimated maximum expected allele frequency for a pathogenic ARX variant of 0.00141. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available (ie, clinical and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."

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