Submissions for variant NM_025137.4(SPG11):c.6223_6224insGAA (p.Phe2074_Asn2075insArg)

dbSNP: rs773225085

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693478	SCV000821349	uncertain significance	Hereditary spastic paraplegia 11	2025-01-06	criteria provided, single submitter	clinical testing	This variant, c.6223_6224insGAA, results in the insertion of 1 amino acid(s) of the SPG11 protein (p.Phe2074_Asn2075insArg), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs773225085, gnomAD 0.1%). This variant has been observed in individual(s) with clinical features of amyotrophic lateral sclerosis (PMID: 32166880). ClinVar contains an entry for this variant (Variation ID: 572161). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Baylor Genetics	RCV001331385	SCV001523418	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X	2020-11-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV002468007	SCV002763736	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001331385	SCV002763737	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000693478	SCV002763738	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000693478	SCV004047600	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing	The inframe insertion variant c.6223_6224insGAA (p.Phe2074_Asn2075insArg) in SPG11 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Phe2074_Asn2075insArg variant has allele frequency 0.008% in gnomAD exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The insertion of amino acid Arg between amino acids Phe at position 2074 and Asn at position 2075 changing protein sequence and it might alter its composition and physico-chemical properties. The observed variant is not in repeat region. For these reasons, this variant has been classified as Uncertain Significance (VUS).