Submissions for variant NM_014363.6(SACS):c.8339T>G (p.Phe2780Cys)

gnomAD frequency: 0.00332  dbSNP: rs111540787

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083821	SCV000289960	likely benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000676358	SCV000338367	uncertain significance	not provided	2015-12-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000341299	SCV000383324	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	RCV000676358	SCV000614985	benign	not provided	2018-09-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000676358	SCV001148937	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	SACS: PP3, BS2
Genome-Nilou Lab	RCV000341299	SCV001653467	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000676358	SCV001819878	likely benign	not provided	2020-03-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29482223, 29538656, 23280630, 28535259)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847977	SCV002105096	uncertain significance	Hereditary spastic paraplegia	2020-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222460	SCV002500357	likely benign	not specified	2022-03-13	criteria provided, single submitter	clinical testing	Variant summary: SACS c.8339T>G (p.Phe2780Cys) 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 allele was found at a frequency of 0.0029 in 250866 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0029 vs 0.0079), allowing no conclusion about variant significance. c.8339T>G has been reported in the literature as segregating in cis with a different putative pathogenic variant (c.12416T>C, p.Leu4139Ser) in a family of five compound heterozygous individuals affected with Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) who harbored c.11675C>G, p.Ser3892* on the other allele (example, Parkinson_2018). The authors cited this variant's frequency and homozygosity in population databases as a rationale for unlikely to be pathogenic. It has also been reported as a non-informative genotype (phase not specified) in at-least one individual sequenced in a cohort of individuals with undiagnosed cerebellar ataxia (example, Coutelier_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000676358	SCV000802134	uncertain significance	not provided	2016-03-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000341299	SCV001455925	likely benign	Charlevoix-Saguenay spastic ataxia	2020-01-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003929987	SCV004740438	likely benign	SACS-related disorder	2022-02-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).