Submissions for variant NM_025137.4(SPG11):c.3453+5A>G

gnomAD frequency: 0.00001  dbSNP: rs983973496

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431719	SCV000534996	likely benign	not specified	2017-01-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV001117294	SCV001275470	uncertain significance	Hereditary spastic paraplegia 11	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.
CeGaT Center for Human Genetics Tuebingen	RCV001531201	SCV001746211	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing	SPG11: PM2, BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001117294	SCV002145457	uncertain significance	Hereditary spastic paraplegia 11	2022-05-25	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the SPG11 gene. It does not directly change the encoded amino acid sequence of the SPG11 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 391841). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003899895	SCV004713486	likely benign	SPG11-related disorder	2020-10-14	criteria provided, single submitter	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).
Ambry Genetics	RCV004022497	SCV004955035	uncertain significance	Inborn genetic diseases	2023-09-25	criteria provided, single submitter	clinical testing	The c.3453+5A>G intronic alteration consists of a A to G substitution nucleotides after coding exon 19 in the SPG11 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.