ClinVar Miner

Submissions for variant NM_001127713.1(ATL1):c.1222A>G (p.Met408Val) (rs28939094)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000004599 SCV000953192 likely pathogenic Hereditary spastic paraplegia 3A 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 408 of the ATL1 protein (p.Met408Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hereditary spastic paraplegia in a family (PMID: 12939451). ClinVar contains an entry for this variant (Variation ID: 4351). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. The observation of one or more missense substitutions at this codon (p.Met408Val and p.Met408Thr) in affected individuals suggests that this may be a clinically significant residue (PMID: 12939451, 17502470). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000004599 SCV000024773 pathogenic Hereditary spastic paraplegia 3A 2003-08-26 no assertion criteria provided literature only
GeneReviews RCV000004599 SCV000041286 pathologic Hereditary spastic paraplegia 3A 2010-09-21 no assertion criteria provided curation Converted during submission to Pathogenic.

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