ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.1126A>G (p.Asn376Asp)

gnomAD frequency: 0.00041  dbSNP: rs199765540
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443429 SCV000529006 likely benign not specified 2018-01-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000543601 SCV000642209 uncertain significance Hereditary spastic paraplegia 11 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 376 of the SPG11 protein (p.Asn376Asp). This variant is present in population databases (rs199765540, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 387116). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics RCV002446710 SCV002753489 uncertain significance Inborn genetic diseases 2021-03-03 criteria provided, single submitter clinical testing The p.N376D variant (also known as c.1126A>G), located in coding exon 6 of the SPG11 gene, results from an A to G substitution at nucleotide position 1126. The asparagine at codon 376 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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