Submissions for variant NM_025137.4(SPG11):c.5135T>G (p.Met1712Arg)

dbSNP: rs1555448989

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552827	SCV000642247	uncertain significance	Hereditary spastic paraplegia 11	2023-03-02	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SPG11 protein function. ClinVar contains an entry for this variant (Variation ID: 466536). This missense change has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1712 of the SPG11 protein (p.Met1712Arg).
GeneDx	RCV001755844	SCV001985499	uncertain significance	not provided	2025-03-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV002467872	SCV002763852	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467873	SCV002763853	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000552827	SCV002763854	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004024023	SCV004955052	uncertain significance	Inborn genetic diseases	2023-10-05	criteria provided, single submitter	clinical testing	The c.5135T>G (p.M1712R) alteration is located in exon 30 (coding exon 30) of the SPG11 gene. This alteration results from a T to G substitution at nucleotide position 5135, causing the methionine (M) at amino acid position 1712 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.