Submissions for variant NM_014363.6(SACS):c.623G>T (p.Ser208Ile)

gnomAD frequency: 0.00001  dbSNP: rs911764681

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522663	SCV000618957	likely pathogenic	not provided	2017-07-14	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the SACS gene. The S208I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S208I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S208I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S208I as a likely pathogenic variant.
Counsyl	RCV000674847	SCV000800248	uncertain significance	Charlevoix-Saguenay spastic ataxia	2018-05-30	criteria provided, single submitter	clinical testing
Invitae	RCV001224412	SCV001396604	likely pathogenic	Spastic paraplegia	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 208 of the SACS protein (p.Ser208Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 450379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SACS protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000674847	SCV002026693	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323587	SCV004029095	uncertain significance	not specified	2023-07-28	criteria provided, single submitter	clinical testing	Variant summary: SACS c.623G>T (p.Ser208Ile) 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 was absent in 248756 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.623G>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as a variant of uncertain significance and two classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.