Submissions for variant NM_014363.6(SACS):c.6952G>A (p.Ala2318Thr)

gnomAD frequency: 0.00022  dbSNP: rs147949881

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000371368	SCV000383333	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.
Athena Diagnostics Inc	RCV000712986	SCV000843546	likely benign	not provided	2022-08-23	criteria provided, single submitter	clinical testing
Invitae	RCV001247269	SCV001420679	likely benign	Spastic paraplegia	2024-02-01	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001642968	SCV001519279	uncertain significance	Spastic ataxia	2021-01-04	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000371368	SCV002026621	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000712986	SCV002056025	uncertain significance	not provided	2022-01-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848099	SCV002105073	uncertain significance	Hereditary spastic paraplegia	2019-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002520865	SCV003715735	uncertain significance	Inborn genetic diseases	2021-06-29	criteria provided, single submitter	clinical testing	The c.6952G>A (p.A2318T) alteration is located in exon 10 (coding exon 9) of the SACS gene. This alteration results from a G to A substitution at nucleotide position 6952, causing the alanine (A) at amino acid position 2318 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000371368	SCV004100424	uncertain significance	Charlevoix-Saguenay spastic ataxia		criteria provided, single submitter	clinical testing	The missense variant p.A2318T in SACS (NM_014363.6) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. It has been submitted to ClinVar with varying interpretations of pathogenicity- Uncertain Significance/ Likely Benign., however no details are available for independent assessment. The p.A2318T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 2318 of SACS is conserved in all mammalian species. The nucleotide c.6952 in SACS is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Natera, Inc.	RCV000371368	SCV001460048	uncertain significance	Charlevoix-Saguenay spastic ataxia	2019-12-24	no assertion criteria provided	clinical testing