ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.2275G>A (p.Ala759Thr) (rs140769107)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766856 SCV000252333 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing The A759T sequence change has been reported as a variant of uncertain significance in an individual with spastic parapesis where a second mutation was not identified (Brugman et al., 2008). The amino acid change is non-conservative in that a non-polar Alanine residue is replaced by a polar Threonine residue. This change occurs at a position in the SPG7 gene that is not highly conserved, and multiple in-silico analysis models predict that A759T is a benign sequence change. Therefore, based on the currently available information it is unclear whether A759T is a disease-causing mutation or a rare benign variant.
Invitae RCV000227318 SCV000287875 uncertain significance Hereditary spastic paraplegia 7 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 759 of the SPG7 protein (p.Ala759Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs140769107, ExAC 0.08%). ClinVar contains an entry for this variant (Variation ID: 215219). This variant has been reported in individuals affected with spastic paraplegia (PMID: 18799786, 21623769). Segregation studies were not performed and the clinical significance of these findings were not determined. 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. Additionally, the threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Athena Diagnostics Inc RCV000200735 SCV000615436 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000227318 SCV000896579 uncertain significance Hereditary spastic paraplegia 7 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000227318 SCV001276493 uncertain significance Hereditary spastic paraplegia 7 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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