Submissions for variant NM_014363.6(SACS):c.3427C>A (p.Gln1143Lys)

dbSNP: rs144267558

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193535	SCV000248783	uncertain significance	not specified	2015-02-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000338267	SCV000383361	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	RCV001083422	SCV000552966	likely benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000470007	SCV001148949	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	SACS: BP4
Athena Diagnostics	RCV000193535	SCV001476813	benign	not specified	2020-08-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000338267	SCV001519937	uncertain significance	Charlevoix-Saguenay spastic ataxia	2020-07-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000338267	SCV002026655	likely benign	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193535	SCV002103869	uncertain significance	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: SACS c.3427C>A (p.Gln1143Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251066 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0011 vs 0.0079), allowing no conclusion about variant significance. c.3427C>A has been reported in the literature in at-least one individual in a study of 171 individuals with ataxia of unknown etiology who underwent exome sequencing (example, Sun_2019). The reported individual did not present with Ataxia and had no supportive Brain MRI findings but had spastic paraplegia and lower extremity spasticity with no known family history. These report(s) do 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847871	SCV002105031	likely benign	Hereditary spastic paraplegia	2021-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000470007	SCV002504294	likely benign	not provided	2019-03-29	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Mayo Clinic Laboratories, Mayo Clinic	RCV000470007	SCV002541567	uncertain significance	not provided	2022-06-17	criteria provided, single submitter	clinical testing	BP4
Ambry Genetics	RCV004020340	SCV004943957	likely benign	Inborn genetic diseases	2021-09-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003907705	SCV004720645	likely benign	SACS-related disorder	2020-11-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).