Submissions for variant NM_025137.4(SPG11):c.7189A>C (p.Asn2397His)

gnomAD frequency: 0.00004  dbSNP: rs779892720

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642585	SCV000764272	uncertain significance	Hereditary spastic paraplegia 11	2022-03-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 2397 of the SPG11 protein (p.Asn2397His). This variant is present in population databases (rs779892720, gnomAD 0.004%). 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: 534887). 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: "Probably 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.
Illumina Laboratory Services, Illumina	RCV000642585	SCV001277053	uncertain significance	Hereditary spastic paraplegia 11	2018-01-12	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.
Genome-Nilou Lab	RCV002467969	SCV002763263	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467970	SCV002763274	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000642585	SCV002763285	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002544668	SCV003555253	uncertain significance	Inborn genetic diseases	2022-09-14	criteria provided, single submitter	clinical testing	The c.7189A>C (p.N2397H) alteration is located in exon 40 (coding exon 40) of the SPG11 gene. This alteration results from a A to C substitution at nucleotide position 7189, causing the asparagine (N) at amino acid position 2397 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.