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

gnomAD frequency: 0.00008  dbSNP: rs747676277

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247856	SCV001421307	benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269831	SCV001450123	uncertain significance	not provided	2024-01-26	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)
Genome-Nilou Lab	RCV001115054	SCV002026615	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847161	SCV002105081	uncertain significance	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387965	SCV004099614	uncertain significance	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: SACS c.7394C>T (p.Ser2465Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251002 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (5.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.7394C>T has been reported in the literature in at least one compound heterozygous individual affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (e.g., Ricca_2019). However, due to the presence of another SACS variant in cis, this report does not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30680480). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; six submitters classified the variant as a variant of uncertain signficance, while one classified it as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV001269831	SCV004136805	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	SACS: PM2, PP3
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV001115054	SCV005044608	uncertain significance	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Natera, Inc.	RCV001115054	SCV002086219	uncertain significance	Charlevoix-Saguenay spastic ataxia	2020-03-03	no assertion criteria provided	clinical testing