ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.6157G>A (p.Val2053Met)

gnomAD frequency: 0.00006  dbSNP: rs149003934
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000594035 SCV000708411 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing
Invitae RCV000034242 SCV000764241 likely pathogenic Hereditary spastic paraplegia 11 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2053 of the SPG11 protein (p.Val2053Met). This variant is present in population databases (rs149003934, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of SPG11-related conditions (PMID: 17717710, 19196735, 20110243, 24833714, 34153142, 35752680). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41341). 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 expected to disrupt SPG11 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina RCV000034242 SCV000915676 uncertain significance Hereditary spastic paraplegia 11 2018-12-03 criteria provided, single submitter clinical testing The SPG11 c.6157G>A (p.Val2053Met) variant has been reported in at least three studies and is found in three unrelated individuals with spastic paraplegia including two patients in a homozygous state and one patient in compound heterozygous state with a second nonsense variant (Del Bo et al. 2007; Crimella et al. 2009; Pensato et al. 2014). Individuals homozygous for the p.Val2053Met variant were also homozygous for the c.733_734delAT (p.Met245ValfsTer2) variant (Del Bo et al. 2007; Pensato et al. 2014). The p.Val2053Met variant was absent from 384 healthy controls (Del Bo et al. 2007; Pensato et al. 2014) and is reported at a frequency of 0.00023 in the total population of the Exome Sequencing Project. Based on the evidence, the p.Val2053Met variant is classified as a variant of unknown significance but suspicious for pathogenicity for spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mayo Clinic Laboratories, Mayo Clinic RCV000594035 SCV001713699 uncertain significance not provided 2020-10-23 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002467533 SCV002763746 uncertain significance Amyotrophic lateral sclerosis type 5 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002467534 SCV002763747 uncertain significance Charcot-Marie-Tooth disease axonal type 2X criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000034242 SCV002763748 uncertain significance Hereditary spastic paraplegia 11 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477051 SCV002788059 uncertain significance Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X 2022-03-08 criteria provided, single submitter clinical testing
GeneReviews RCV000034242 SCV000058182 not provided Hereditary spastic paraplegia 11 no assertion provided literature only

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