Submissions for variant NM_014363.6(SACS):c.8393C>A (p.Pro2798Gln)

gnomAD frequency: 0.00178  dbSNP: rs140551762

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001815246	SCV000248787	uncertain significance	not specified	2021-11-22	criteria provided, single submitter	clinical testing
Invitae	RCV000230214	SCV000289962	benign	Spastic paraplegia	2024-01-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000513770	SCV000331577	uncertain significance	not provided	2015-09-21	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513770	SCV000610377	uncertain significance	not provided	2017-06-20	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000513770	SCV000614988	likely benign	not provided	2020-03-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513770	SCV000780455	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	SACS: PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000513770	SCV000802133	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	BS1, PM3_supporting
Illumina Laboratory Services, Illumina	RCV000194652	SCV001266629	uncertain significance	Charlevoix-Saguenay spastic ataxia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000513770	SCV001450121	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000194652	SCV001529507	uncertain significance	Charlevoix-Saguenay spastic ataxia	2018-07-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000513770	SCV001771583	likely benign	not provided	2020-12-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20876471, 25401298, 27433545, 23280630)
Genome-Nilou Lab	RCV000194652	SCV002026601	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847873	SCV002105099	uncertain significance	Hereditary spastic paraplegia	2021-05-25	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000194652	SCV003820618	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-06-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001815246	SCV004241939	likely benign	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: SACS c.8393C>A (p.Pro2798Gln) 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 0.0026 in 1613592 control chromosomes in the gnomAD database.. Although this frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0026 vs 0.0079), it was found in 7 homozygotes, suggesting the variant is likely a benign polymorphism. c.8393C>A has been reported in the literature in the homozygous state in three siblings affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay, however, they also had another putatively pathogenic variant in homozygosity (Baets_2010). Therefore, 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 publications have been ascertained in the context of this evaluation (PMID: 20876471, 25401298). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Ten submitters classified the variant as uncertain significance and three classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000513770	SCV001739905	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513770	SCV001956571	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513770	SCV001975212	uncertain significance	not provided		no assertion criteria provided	clinical testing