Submissions for variant NM_025137.4(SPG11):c.1551_1552del (p.Cys518fs)

dbSNP: rs312262730

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000034176	SCV000915679	uncertain significance	Hereditary spastic paraplegia 11	2018-10-30	criteria provided, single submitter	clinical testing	The SPG11 c.1551_1552delTT (p.Cys518SerfsTer39) variant is a frameshift variant and is predicted to result in a premature truncation of the protein. The p.Cys518SerfsTer39 variant, also reported as p.Leu517ValfsTer16 in literature, has been reported in two studies, in which it is found in a total of three individuals with spastic paraplegia, including in two siblings in a compound heterozygous state, and in one in a heterozygous state in whom a second variant was not identified (Samaranch et al. 2008; Zhang et al. 2016). In one family, two affected siblings presented with autosomal recessive hereditary spastic paraplegia with thin corpus callosum. The variant was absent from 100 Chinese control subjects. The p.Cys518SerfsTer39 variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage, and so the variant is presumed to be rare. Based on the predicted truncating nature of the variant and limited evidence, the p.Cys518SerfsTer39 variants classified as a variant of unknown significance but suspicious for autosomal recessive spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034176	SCV004296963	pathogenic	Hereditary spastic paraplegia 11	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys518Serfs*39) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 18663179). This variant is also known as c.1550_1551delTT (p.L517fsX556). ClinVar contains an entry for this variant (Variation ID: 41275). For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000034176	SCV000058114	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only