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

gnomAD frequency: 0.00001  dbSNP: rs1160357920

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-03-27	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000578242	SCV005044595	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research