Submissions for variant NM_014363.6(SACS):c.10126G>A (p.Ala3376Thr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002952956	SCV003272389	uncertain significance	Spastic paraplegia	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 3376 of the SACS protein (p.Ala3376Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs761454766, ExAC 0.002%). This variant has not been reported in the literature in individuals with SACS-related conditions. 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) performed at Invitae indicates that this missense variant is not expected to disrupt SACS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV003138408	SCV003820625	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004067273	SCV004944902	likely benign	Inborn genetic diseases	2023-12-21	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.