ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.3391C>T (p.Leu1131Phe)

gnomAD frequency: 0.00001  dbSNP: rs139805032
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000232090 SCV000289957 uncertain significance Spastic paraplegia 2024-08-28 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1131 of the SACS protein (p.Leu1131Phe). This variant is present in population databases (rs139805032, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of hereditary spastic paraplegia (internal data). ClinVar contains an entry for this variant (Variation ID: 240899). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SACS protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000988965 SCV001138918 likely pathogenic Charlevoix-Saguenay spastic ataxia 2019-05-28 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000988965 SCV002026657 uncertain significance Charlevoix-Saguenay spastic ataxia 2021-09-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586646 SCV005076926 uncertain significance not specified 2024-04-08 criteria provided, single submitter clinical testing Variant summary: SACS c.3391C>T (p.Leu1131Phe) 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 was absent in 249570 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.3391C>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 240899). Based on the evidence outlined above, the variant was classified as uncertain significance.

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