ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.2926C>A (p.Arg976Ser) (rs139993038)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516574 SCV000614947 uncertain significance not provided 2017-04-28 criteria provided, single submitter clinical testing
Invitae RCV001081341 SCV001004581 likely benign Spastic paraplegia 2020-12-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109615 SCV001266969 uncertain significance Charlevoix-Saguenay spastic ataxia 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000516574 SCV001549454 uncertain significance not provided no assertion criteria provided clinical testing The SACS p.Arg976Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs139993038) and ClinVar (classified as a VUS by Athena Diagnostics Inc). The variant was also identified in control databases in 110 of 282716 chromosomes at a frequency of 0.000389 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 105 of 24960 chromosomes (freq: 0.004207), Latino in 4 of 35424 chromosomes (freq: 0.000113) and European (non-Finnish) in 1 of 129084 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Arg976 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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