Submissions for variant NM_014363.6(SACS):c.815G>A (p.Arg272His)

dbSNP: rs745907077

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670029	SCV000794840	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2017-10-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855535	SCV002147683	pathogenic	Spastic paraplegia	2020-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 272 of the SACS protein (p.Arg272His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs745907077, ExAC 0.001%). This variant has been observed in individual(s) with clinical features of spastic ataxia of Charlevoix-Saguenay (ARSACS) (PMID: 23338241, 26288984). ClinVar contains an entry for this variant (Variation ID: 554404). 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 expected to disrupt SACS protein function. This variant disrupts the p.Arg272 amino acid residue in SACS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19892370, 30901567). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000670029	SCV004210024	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2023-02-23	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000670029	SCV005061967	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670029	SCV005726763	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: SACS c.815G>A (p.Arg272His) 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 allele was found at a frequency of 4e-06 in 251436 control chromosomes. c.815G>A has been reported in the literature in multiple homozygous individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (Dibilio_2013, Pilliod_2015). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.814C>T, p.Arg272Cys), supporting the critical relevance of codon 272 to SACS protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23338241, 26288984). ClinVar contains an entry for this variant (Variation ID: 554404). Based on the evidence outlined above, the variant was classified as pathogenic.
Solve-RD Consortium	RCV000670029	SCV005091370	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team