ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.733_734del (p.Met245fs) (rs312262720)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000001171 SCV000259624 pathogenic Spastic paraplegia 11, autosomal recessive 2019-12-15 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides in exon 4 of the SPG11 mRNA (c.733_734delAT), causing a frameshift at codon 245. This creates a premature translational stop signal (p.Met245Valfs*2) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic. This particular variant has been reported in many individuals affected with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC (PMID: 17322883, 17717710, 18067136, 18079167, 18332254, 18835492, 19105190, 19438933, 22175763, 22237444, 22696581, 24833714, 27071356). It has also been reported in two siblings affected with juvenile amyotrophic lateral sclerosis (PMID: 20110243). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000256068 SCV000322440 pathogenic not provided 2017-11-08 criteria provided, single submitter clinical testing The c.733_734delAT pathogenic variant in the SPG11 gene has been reported previously in association with autosomal recessive spastic paraplegia when present in the homozygous state or when in trans with another pathogenic variant (Stevanin et al., 2007; Boukhris et al., 2008). The c.733_734delAT variant causes a frameshift starting with codon Methionine 245, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Met245ValfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.733_734delAT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.733_734delAT as a pathogenic variant.
Unit for Genetic & Epidemiological Research on Neurological Disorders,Instituto de Investigação e Inovação em Saúde RCV000515921 SCV000574449 pathogenic Hereditary spastic paraplegia 2017-03-07 criteria provided, single submitter research
Broad Institute Rare Disease Group,Broad Institute RCV000001171 SCV001164580 pathogenic Spastic paraplegia 11, autosomal recessive 2018-12-03 criteria provided, single submitter research The heterozygous p.Met245ValfsTer2 variant in SPG11 was identified by our study in the compound heterozygous state, along with another pathogenic variant, in two siblings with spastic paraplegia. The presence of this variant in combination with a reported pathogenic variant and in an individual with spastic paraplegia increases the likelihood that the p.Met245ValfsTer2 variant is pathogenic. The p.Met245ValfsTer2 variant in SPG11 has been well-reported in the literature. This variant has been reported in greater than 22 individuals from Italy, Japan, France, Tunisia, Sicily, Korea, Spain, China, and Portugal with spastic paraplegia in the homozygous and compound heterozygous state, segregated with disease in 12 affected relatives from 5 families (PMID: 17717710, 20110243, 17322883, 18079167, 22175763, 18332254, 24833714, 22696581, 22237444, 18067136, 18835492), but has been identified in 0.006133% (17/277208) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs312262720). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1112). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 245 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SPG11 gene is an established disease mechanism in autosomal recessive spastic paraplegia. In summary, the p.Met245ValfsTer2variant is pathogenic based off of our findings, multiple reports of pathogenicity in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PVS1, PM3, PP1_Moderate (Richards 2015).
OMIM RCV000001171 SCV000021321 pathogenic Spastic paraplegia 11, autosomal recessive 2010-02-01 no assertion criteria provided literature only
GeneReviews RCV000001171 SCV000058206 pathologic Spastic paraplegia 11, autosomal recessive 2013-01-31 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000193699 SCV000249579 pathogenic Amyotrophic lateral sclerosis type 5 2010-02-01 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000001171 SCV000678246 likely pathogenic Spastic paraplegia 11, autosomal recessive 2018-01-01 no assertion criteria provided clinical testing The observed variant c.733_734delAT (p.M245Vfs) is not reported in The 1000 Genomes database and its minor allele frequency in ExAC database is 0.0001071. The in silico prediction for the variant is pathogenic by MutationTaster2.

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