Submissions for variant NM_014363.6(SACS):c.110G>A (p.Arg37His)

gnomAD frequency: 0.00006  dbSNP: rs866539724

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522808	SCV000619215	uncertain significance	not provided	2019-06-29	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center	RCV001834696	SCV002548930	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-09-03	criteria provided, single submitter	clinical testing	The c.110G>A (p.Arg37His) variant identified in the SACS gene substitutes a moderately conserved Arginine for Histidine at amino acid 37/4580 (exon 3/10). This variant is found with low frequency in gnomAD(v3.1.1)(7 heterozygotes, 0 homozygotes; allele frequency:4.60e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Tolerated (SIFT; score: 0.138) and Benign (REVEL;score:0.1159) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:445133), and to our current knowledge has not been reported in affected individuals in the literature. The p.Arg37residue is within the ubiquitin-like domain of SACS (UniProtKB:Q9NZJ4). Given the lack of compelling evidence for its pathogenicity, the c.110G>A (p.Arg37His) variant identified in the SACS gene is reported as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525178	SCV003294862	likely benign	Spastic paraplegia	2024-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004023576	SCV004944906	uncertain significance	Inborn genetic diseases	2023-09-26	criteria provided, single submitter	clinical testing	The c.110G>A (p.R37H) alteration is located in exon 3 (coding exon 2) of the SACS gene. This alteration results from a G to A substitution at nucleotide position 110, causing the arginine (R) at amino acid position 37 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056119	SCV005725852	uncertain significance	not specified	2024-11-29	criteria provided, single submitter	clinical testing	Variant summary: SACS c.110G>A (p.Arg37His) results in a non-conservative amino acid change located in the Ubiquitin-like domain (IPR029071) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 101734 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.110G>A in individuals affected with Charlevoix-Saguenay spastic ataxia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 450612). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001834696	SCV002086763	uncertain significance	Charlevoix-Saguenay spastic ataxia	2019-11-11	no assertion criteria provided	clinical testing