ClinVar Miner

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

gnomAD frequency: 0.00005  dbSNP: rs312262720
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000001171 SCV000259624 pathogenic Hereditary spastic paraplegia 11 2021-11-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met245Valfs*2) 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 present in population databases (rs312262720, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive hereditary spastic paraplegia with thin corpus callosum, also known as ARHSP-TCC and juvenile amyotrophic lateral sclerosis (PMID: 17322883, 17717710, 18067136, 18079167, 18332254, 18835492, 19105190, 19438933, 20110243, 22175763, 22237444, 22696581, 24833714, 27071356). ClinVar contains an entry for this variant (Variation ID: 1112). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000256068 SCV000322440 pathogenic not provided 2021-11-02 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17717710, 18332254, 20110243, 22175763, 17322883, 18067136, 27071356, 31227335, 31289639, 31969655, 29980238, 31589614)
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 Hereditary spastic paraplegia 11 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).
Ambry Genetics RCV001266812 SCV001444991 pathogenic Inborn genetic diseases 2019-12-04 criteria provided, single submitter clinical testing
Paris Brain Institute,Inserm - ICM RCV000001171 SCV001451240 pathogenic Hereditary spastic paraplegia 11 criteria provided, single submitter clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center RCV001813928 SCV001755640 pathogenic Abnormal central motor function 2021-07-10 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000515921 SCV002105782 pathogenic Hereditary spastic paraplegia 2022-01-14 criteria provided, single submitter clinical testing
OMIM RCV000001171 SCV000021321 pathogenic Hereditary spastic paraplegia 11 2010-02-01 no assertion criteria provided literature only
GeneReviews RCV000001171 SCV000058206 pathologic Hereditary spastic paraplegia 11 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 Hereditary spastic paraplegia 11 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.
GenomeConnect - Invitae Patient Insights Network RCV001535461 SCV001749380 not provided Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 05-07-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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