Submissions for variant NM_025137.4(SPG11):c.3508C>A (p.Leu1170Ile)

dbSNP: rs534771304

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001117292	SCV001275468	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001117292	SCV002199398	uncertain significance	Hereditary spastic paraplegia 11	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1170 of the SPG11 protein (p.Leu1170Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 32989326). ClinVar contains an entry for this variant (Variation ID: 885627). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Genome-Nilou Lab	RCV002468157	SCV002763977	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002468158	SCV002763978	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001117292	SCV002763979	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing