ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.1033C>T (p.Arg345Trp)

gnomAD frequency: 0.00011  dbSNP: rs776156836
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000466492 SCV000552968 benign Spastic paraplegia 2024-10-15 criteria provided, single submitter clinical testing
GeneDx RCV000519338 SCV000619216 uncertain significance not provided 2019-06-29 criteria provided, single submitter clinical testing 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
Genome-Nilou Lab RCV001271972 SCV002026547 uncertain significance Charlevoix-Saguenay spastic ataxia 2021-09-05 criteria provided, single submitter clinical testing
New York Genome Center RCV001271972 SCV002548929 uncertain significance Charlevoix-Saguenay spastic ataxia 2021-09-03 criteria provided, single submitter clinical testing The c.1033C>T (p.Arg345Trp) variant identified in the SACS gene substitutes a well conserved Arginine for Tryptophan at amino acid 345/4580 (exon 8/10). This variant is found with low frequency in gnomAD(v3.1.1)(16 heterozygotes, 0 homozygotes; allele frequency: 1.05e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL;score:0.6349) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:411689), and to our current knowledge has not been reported in affected individuals in the literature. The p.Arg345 residue is not within a mapped domain of SACS (UniProtKB:Q9NZJ4). Given the lack of compelling evidence for its pathogenicity, the c.1033C>T (p.Arg345Trp) variant identified in the SACS gene is reported as a Variant of Uncertain Significance.
Ambry Genetics RCV004022883 SCV004944903 uncertain significance Inborn genetic diseases 2023-09-26 criteria provided, single submitter clinical testing The c.1033C>T (p.R345W) alteration is located in exon 8 (coding exon 7) of the SACS gene. This alteration results from a C to T substitution at nucleotide position 1033, causing the arginine (R) at amino acid position 345 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.006% (15/251392) total alleles studied. The highest observed frequency was 0.02% (6/30612) of South Asian alleles. This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV005056027 SCV005725831 uncertain significance not specified 2024-11-29 criteria provided, single submitter clinical testing Variant summary: SACS c.1033C>T (p.Arg345Trp) 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 6e-05 in 251392 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Charlevoix-Saguenay spastic ataxia, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1033C>T 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: 411689). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001271972 SCV001453566 uncertain significance Charlevoix-Saguenay spastic ataxia 2020-09-16 no assertion criteria provided clinical testing

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