ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.4744G>A (p.Asp1582Asn)

gnomAD frequency: 0.00001  dbSNP: rs1160357920
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536906 SCV000629469 pathogenic Spastic paraplegia 2023-01-23 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 458265). This missense change has been observed in individuals with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 23250129). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1582 of the SACS protein (p.Asp1582Asn). Studies have shown that this missense change alters SACS gene expression (PMID: 23250129). For these reasons, this variant has been classified as Pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV000578242 SCV000680360 likely pathogenic Charlevoix-Saguenay spastic ataxia 2017-11-08 criteria provided, single submitter clinical testing
Counsyl RCV000578242 SCV000794598 likely pathogenic Charlevoix-Saguenay spastic ataxia 2017-10-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000578242 SCV000893322 pathogenic Charlevoix-Saguenay spastic ataxia 2018-10-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000578242 SCV002027658 pathogenic Charlevoix-Saguenay spastic ataxia 2021-09-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001848923 SCV002105044 pathogenic Hereditary spastic paraplegia 2016-12-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000578242 SCV002511802 pathogenic Charlevoix-Saguenay spastic ataxia 2022-04-29 criteria provided, single submitter clinical testing Variant summary: SACS c.4744G>A (p.Asp1582Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-06 in 150864 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.4744G>A, has been reported in the literature in multiple compound heterozygous individuals affected with typical Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), who carried the French-Canadian founder mutation (c.8844delT (p.Ile2949PhefsX4)) in trans (Thiffault_2013, Briand_2019). Western blot analysis of lymphoblast samples from one of these patients demonstrated a severe decrease in sacsin protein amount (Thiffault_2013). In addition, the variant was also reported in homozygous form in two siblings who were diagnosed with isolated (non-syndromic) motor and sensory neuropathy (Vill_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000578242 SCV004209953 pathogenic Charlevoix-Saguenay spastic ataxia 2023-07-21 criteria provided, single submitter clinical testing

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