Submissions for variant NM_014363.6(SACS):c.1912T>G (p.Cys638Gly)

gnomAD frequency: 0.00008  dbSNP: rs200333323

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000306464	SCV000383372	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	RCV001288709	SCV001476020	likely benign	not provided	2020-02-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001400059	SCV001601860	likely benign	Spastic paraplegia	2024-03-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000306464	SCV002026677	likely benign	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848105	SCV002105004	uncertain significance	Hereditary spastic paraplegia	2017-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004955414	SCV005498775	likely benign	Inborn genetic diseases	2024-08-02	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	RCV004748724	SCV005360044	uncertain significance	SACS-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The SACS c.1912T>G variant is predicted to result in the amino acid substitution p.Cys638Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.