ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.8108G>A (p.Arg2703His)

gnomAD frequency: 0.00001  dbSNP: rs750181262
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668456 SCV000793063 uncertain significance Charlevoix-Saguenay spastic ataxia 2017-08-02 criteria provided, single submitter clinical testing
GeneDx RCV001576889 SCV001804162 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29482223, 26288984)
Genome-Nilou Lab RCV000668456 SCV002026505 uncertain significance Charlevoix-Saguenay spastic ataxia 2021-09-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001868222 SCV002238295 pathogenic Spastic paraplegia 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2703 of the SACS protein (p.Arg2703His). This variant is present in population databases (rs750181262, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 26288984; Invitae). ClinVar contains an entry for this variant (Variation ID: 553081). 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. This variant disrupts the p.Arg2703 amino acid residue in SACS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16007637, 29277257). 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 RCV000668456 SCV004210023 likely pathogenic Charlevoix-Saguenay spastic ataxia 2024-03-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000668456 SCV002086215 uncertain significance Charlevoix-Saguenay spastic ataxia 2020-08-14 no assertion criteria provided clinical testing

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