Submissions for variant NM_025137.4(SPG11):c.789A>G (p.Lys263=)

gnomAD frequency: 0.00006  dbSNP: rs764439012

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244779	SCV001418023	benign	Hereditary spastic paraplegia 11	2024-12-08	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002221269	SCV002498603	uncertain significance	Amyotrophic lateral sclerosis	2021-07-02	criteria provided, single submitter	clinical testing	This sequence change is a 'silent' substitution in exon 4 of SPG11, meaning that it does not change the encoded amino acid sequence of the SPG11 protein. The variant is present in a large population cohort at a frequency of 0.006% (rs764439012, 15/251,440 alleles, 0 homozygotes in gnomAD v2.1), with an East Asian allele frequency of 0.08%. It has been reported as a variant of uncertain significance (ClinVar), but has not been reported in the relevant medical literature. Multiple lines of computational evidence predict the creation of a de novo acceptor site (SpliceAI, MaxEntScan, NNSplice), which has not been assessed in RNA studies. Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.
Genome-Nilou Lab	RCV002468204	SCV002764213	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002468205	SCV002764214	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001244779	SCV002764215	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing