Submissions for variant NM_014363.6(SACS):c.1463C>T (p.Pro488Leu) (rs375875022)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000317718	SCV000383378	uncertain significance	Charlevoix-Saguenay spastic ataxia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000464896	SCV000552971	uncertain significance	Spastic paraplegia	2018-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 488 of the SACS protein (p.Pro488Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs375875022, ExAC 0.009%). This variant has not been reported in the literature in individuals with SACS-related disease. ClinVar contains an entry for this variant (Variation ID: 311562). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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	RCV000712962	SCV000843522	uncertain significance	not provided	2019-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000317718	SCV001453564	uncertain significance	Charlevoix-Saguenay spastic ataxia	2020-09-16	no assertion criteria provided	clinical testing