Submissions for variant NM_025137.4(SPG11):c.1270C>A (p.Pro424Thr)

gnomAD frequency: 0.00040  dbSNP: rs141596008

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000185539	SCV000952523	benign	Hereditary spastic paraplegia 11	2024-12-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000185539	SCV001279524	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508762	SCV001715111	uncertain significance	not provided	2020-02-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847822	SCV002105656	uncertain significance	Hereditary spastic paraplegia	2018-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002372141	SCV002684027	uncertain significance	Inborn genetic diseases	2023-03-31	criteria provided, single submitter	clinical testing	The c.1270C>A (p.P424T) alteration is located in exon 6 (coding exon 6) of the SPG11 gene. This alteration results from a C to A substitution at nucleotide position 1270, causing the proline (P) at amino acid position 424 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002467649	SCV002764156	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467650	SCV002764157	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000185539	SCV002764158	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185539	SCV000238417	uncertain significance	Hereditary spastic paraplegia 11	2014-10-14	no assertion criteria provided	research	This test identified a variant (c.1270C>A;p.Pro424Thr) in the SPG11 gene associated with spastic paraplegia 11 (autosomal recessive). This variant is considered a variant of unknown significance. The c.1270C>A;p.Pro424Thr variant has not been reported in literature; however, it was seen in one individual in control databases (EVS 6500 and 1000 Genomes) in the heterozygous form and has not been reported in ClinVar database. The amino acid change (p.Pro424Thr) was observed in the reference genome of one other organism (wallaby). Most common variants reported to be associated with autosomal recessive spastic paraplegia are nonsense, small deletions, or insertions leading to a truncated protein product. Missense variants, such as (c.1270C>A;p.Pro424Thr) have been rarely associated with the condition. A second variant on the other allele was not identified.