Submissions for variant NM_014363.6(SACS):c.13717A>C (p.Asn4573His)

gnomAD frequency: 0.00326  dbSNP: rs34382952

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000254363	SCV000225021	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000254363	SCV000312148	likely benign	not specified		criteria provided, single submitter	clinical testing
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	RCV000515968	SCV000574498	uncertain significance	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000488235	SCV000574947	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SACS: BS2
Athena Diagnostics Inc	RCV000488235	SCV000614938	likely benign	not provided	2018-08-13	criteria provided, single submitter	clinical testing
Invitae	RCV001082378	SCV000629455	likely benign	Spastic paraplegia	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000674768	SCV000800161	benign	Charlevoix-Saguenay spastic ataxia	2018-05-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000674768	SCV001268887	uncertain significance	Charlevoix-Saguenay spastic ataxia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000674768	SCV001653434	likely benign	Charlevoix-Saguenay spastic ataxia	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000488235	SCV001780154	likely benign	not provided	2021-04-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23280630, 22162184, 22287014, 19779133, 28832565)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000674768	SCV001976726	uncertain significance	Charlevoix-Saguenay spastic ataxia	2021-08-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000515968	SCV002104990	likely benign	Hereditary spastic paraplegia	2020-12-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254363	SCV003923058	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: SACS c.13717A>C (p.Asn4573His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 250932 control chromosomes, predominantly at a frequency of 0.0052 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0032 vs 0.0079), allowing no conclusion about variant significance. c.13717A>C has been reported in the literature, primarily in the heterozygous state and in settings of multigene panel testing, in individuals affected with ataxias and other movement disorders, without strong evidence for causality (e.g. Vermeer_2009, Fogel_2012, Morais_2017, Martinez-Rubio_2022, OGorman_2019). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. 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: 22287014, 36233161, 28832565, 31519934, 19779133). Thirteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified it as benign (n=1)/likely benign (n=8), VUS (n=3), or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000488235	SCV000802121	uncertain significance	not provided	2016-03-15	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000674768	SCV001453882	likely benign	Charlevoix-Saguenay spastic ataxia	2020-01-02	no assertion criteria provided	clinical testing