Submissions for variant NM_014363.6(SACS):c.10982C>T (p.Ala3661Val)

gnomAD frequency: 0.00198  dbSNP: rs36061856

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193480	SCV000248780	uncertain significance	not specified	2014-09-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079338	SCV000289948	likely benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000278445	SCV000383303	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.
Athena Diagnostics	RCV000230933	SCV000614927	benign	not provided	2019-06-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000230933	SCV001334477	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SACS: BS1
Pars Genome Lab	RCV000278445	SCV001736762	likely benign	Charlevoix-Saguenay spastic ataxia	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000278445	SCV001806292	likely benign	Charlevoix-Saguenay spastic ataxia	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000230933	SCV001996511	likely benign	not provided	2018-10-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29220673, 29915382)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847870	SCV002104962	likely benign	Hereditary spastic paraplegia	2021-05-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193480	SCV002556155	uncertain significance	not specified	2024-05-08	criteria provided, single submitter	clinical testing	Variant summary: SACS c.10982C>T (p.Ala3661Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 281386 control chromosomes with 2 homozygotes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0011 vs 0.0079), allowing no conclusion about variant significance. c.10982C>T has been reported in the literature in at least one compound heterozygous individual affected with Spastic Paraplegia (Sun_2019). The variant was also found occuring in one compound heterozygous individual affected with intellectual disability (Martin_2017), however, this individual also carried a de novo variant in GRIA4 c.2090G>C [p.Arg697Pro]. GRIA4 associated neurodevelopmental disorders are autosomal dominant (OMIM #617864), and the authors conclude this GRIA4 variant was the cause of the patients phenotype. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29220673, 29915382). ClinVar contains an entry for this variant (Variation ID: 212109). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Natera, Inc.	RCV000278445	SCV001455911	likely benign	Charlevoix-Saguenay spastic ataxia	2020-04-17	no assertion criteria provided	clinical testing