Submissions for variant NM_014946.4(SPAST):c.1735A>C (p.Asn579His)

gnomAD frequency: 0.00031  dbSNP: rs144594804

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193599	SCV000249012	uncertain significance	not specified	2014-06-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000658865	SCV000565590	uncertain significance	not provided	2023-12-21	criteria provided, single submitter	clinical testing	Reported in an individual with an apparently sporadic, adult-onset upper motor neuron syndrome (PMID: 16240363); Reported in two individuals with hereditary spastic paraplegia who harbored a second SPAST variant; however, phase is unknown as parental testing was not performed (PMID: 16055926, 28572275); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20562464, 17594340, 30476002, 24451228, 28572275, 16055926, 34426522, 34445196, 21139634, 26094131, 16240363, 34983064, 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000509114	SCV000645354	likely benign	Hereditary spastic paraplegia 4	2024-11-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658865	SCV000780662	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000509114	SCV001301641	benign	Hereditary spastic paraplegia 4	2017-04-28	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Paris Brain Institute, Inserm - ICM	RCV001391562	SCV001451333	uncertain significance	Spastic paraplegia		criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001640291	SCV001519251	uncertain significance	Spastic ataxia	2021-01-04	criteria provided, single submitter	research
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847874	SCV002105624	uncertain significance	Hereditary spastic paraplegia	2019-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193599	SCV004039461	uncertain significance	not specified	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: SPAST c.1735A>C (p.Asn579His) results in a conservative amino acid change located in the Spastin/Vps4, C-terminal (IPR015415) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 250738 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. c.1735A>C has been reported in the literature in individuals affected with Spastic Paraplegia or hereditary ataxia without strong evidence of causality (Brugman_2005, Depienne_2006, Chelban_2017, Parodi_2018, Gelatolo_2021). These reports do not provide unequivocal conclusions about association of the variant with Spastic Paraplegia 4, Autosomal Dominant. Co-occurrence with another pathogenic/likely pathogenic variant has been reported (SPAST c.1216A>G, p.Ile406Val, Depienne_2006), providing supporting evidence for a benign role. 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: 16240363, 16055926, 28572275, 30476002, 34445196). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4), benign (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect, ClinGen	RCV000509114	SCV000607201	not provided	Hereditary spastic paraplegia 4		flagged submission	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect, ClinGen	RCV000658865	SCV000986750	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as not providedand reported on 04/10/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.