Submissions for variant NM_014946.4(SPAST):c.1676G>A (p.Gly559Asp)

dbSNP: rs864622179

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205236	SCV000259582	pathogenic	Hereditary spastic paraplegia 4	2024-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 559 of the SPAST protein (p.Gly559Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11087788, 11843700, 15248095, 17598600, 20718791, 22960362; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly527Asp, 1583G>A and c.G1801A. ClinVar contains an entry for this variant (Variation ID: 219608). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPAST protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000432874	SCV000521176	likely pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Reported multiple times in individuals with spastic paraplegia (PMID: 20718791, 11087788, 11843700, 22960362); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11087788, 17598600, 11843700, 31285604, 22960362, 15248095, 21139634, 26094131, 35487127, 20718791)
Athena Diagnostics	RCV000432874	SCV000615390	pathogenic	not provided	2024-04-10	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. In some published literature, this variant is referred to as 1801G>A and 1583G>A (Gly527Asp).
SIB Swiss Institute of Bioinformatics	RCV000205236	SCV000883277	likely pathogenic	Hereditary spastic paraplegia 4	2024-12-04	criteria provided, single submitter	curation	This variant is interpreted as likely pathogenic for Spastic paraplegia 4, autosomal dominant. This missense change is absent from large population cohorts (gnomAD v4.1.0; PM2_supporting); it has been observed in multiple unrelated patients (PMID: 11087788, 11843700, 17598600, 20718791; PS4_moderate); computational evidence support a damaging effect on gene or gene product (PP3_moderate REVEL 0.894); this change affects an amino acid residue where a different missense change has been determined to be pathogenic/likely pathogenic (p.Gly559Arg PMID: 22960362, 27688599; PM5_moderate).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847924	SCV002105619	likely pathogenic	Hereditary spastic paraplegia	2021-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000205236	SCV005185088	pathogenic	Hereditary spastic paraplegia 4	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: SPAST c.1676G>A (p.Gly559Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249424 control chromosomes. c.1676G>A has been reported in the literature in multiple individuals affected with utosomal dominant Hereditary Spastic Paraplegia (example, Hentati_2000, Meijer_2002, Meijer_2007, Svenson_2004). These data indicate that the variant is very likely to be associated with disease. 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: 11087788, 11843700, 17598600, 15248095). ClinVar contains an entry for this variant (Variation ID: 219608). Based on the evidence outlined above, the variant was classified as pathogenic.