Submissions for variant NM_014363.6(SACS):c.2580A>G (p.Gln860=)

gnomAD frequency: 0.00031  dbSNP: rs41283958

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000712969	SCV000843529	benign	not provided	2022-04-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765125	SCV000896349	uncertain significance	Charlevoix-Saguenay spastic ataxia	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001087176	SCV001001807	likely benign	Spastic paraplegia	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000765125	SCV001269524	uncertain significance	Charlevoix-Saguenay spastic ataxia	2018-03-16	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.
Baylor Genetics	RCV000765125	SCV001519940	uncertain significance	Charlevoix-Saguenay spastic ataxia	2019-12-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000765125	SCV001712298	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-05-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001849072	SCV002105018	uncertain significance	Hereditary spastic paraplegia	2021-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712969	SCV002545099	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	SACS: BP4, BP7
Natera, Inc.	RCV000765125	SCV001464175	likely benign	Charlevoix-Saguenay spastic ataxia	2020-01-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000712969	SCV001552625	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SACS p.Gln860Gln variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs41283958), ClinVar (classified as a VUS by Athena Diagnostics and Fulgent Genetics) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 85 of 281874 chromosomes (1 homozygous) at a frequency of 0.000302 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 7 of 7184 chromosomes (freq: 0.000974), European (non-Finnish) in 61 of 128904 chromosomes (freq: 0.000473), South Asian in 8 of 30396 chromosomes (freq: 0.000263), Latino in 5 of 35336 chromosomes (freq: 0.000142), African in 3 of 24676 chromosomes (freq: 0.000122) and European (Finnish) in 1 of 25090 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, and East Asian populations. The p.Gln860Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.