ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.7394C>T (p.Ser2465Leu)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001115054 SCV001272993 uncertain significance Charlevoix-Saguenay spastic ataxia 2018-01-13 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 RCV001247856 SCV001421307 uncertain significance Spastic paraplegia 2019-06-05 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 2465 of the SACS protein (p.Ser2465Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs747676277, ExAC 0.02%). This variant has been observed in an individual affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). In this individual this variant was in cis with a p.Leu3916Trp variant and in trans with a p.Leu3916Trp variant in SACS (PMID: 30680480). 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: "Benign"; 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.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV001269831 SCV001450123 likely pathogenic not provided 2014-11-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV001115054 SCV001519942 uncertain significance Charlevoix-Saguenay spastic ataxia 2019-12-20 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001269831 SCV001754130 uncertain significance not provided 2020-05-29 criteria provided, single submitter clinical testing Identified in a patient with a clinical diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay who had another missense variant on the same allele (in cis) as well as a variant on the opposite allele (in trans) (Ricca et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30680480)

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