Submissions for variant NM_014363.6(SACS):c.2926C>A (p.Arg976Ser)

dbSNP: rs139993038

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV001644611	SCV000614947	benign	not specified	2021-02-26	criteria provided, single submitter	clinical testing
Invitae	RCV001081341	SCV001004581	likely benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001109615	SCV001266969	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.
Genome-Nilou Lab	RCV001109615	SCV002026663	likely benign	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848892	SCV002105023	uncertain significance	Hereditary spastic paraplegia	2017-05-29	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001109615	SCV002580702	uncertain significance	Charlevoix-Saguenay spastic ataxia	2022-02-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000516574	SCV004226412	uncertain significance	not provided	2022-09-14	criteria provided, single submitter	clinical testing	BS1
PreventionGenetics, part of Exact Sciences	RCV003905307	SCV004724631	likely benign	SACS-related condition	2022-06-27	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000516574	SCV001549454	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SACS p.Arg976Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs139993038) and ClinVar (classified as a VUS by Athena Diagnostics Inc). The variant was also identified in control databases in 110 of 282716 chromosomes at a frequency of 0.000389 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 105 of 24960 chromosomes (freq: 0.004207), Latino in 4 of 35424 chromosomes (freq: 0.000113) and European (non-Finnish) in 1 of 129084 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Arg976 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.