ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.1939A>G (p.Ile647Val)

gnomAD frequency: 0.00003  dbSNP: rs375256495
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000470611 SCV000545195 uncertain significance Hereditary spastic paraplegia 11 2022-08-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 647 of the SPG11 protein (p.Ile647Val). This variant is present in population databases (rs375256495, gnomAD 0.02%). 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: 406520). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000521530 SCV000621908 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing The I647V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I647V variant is observed in 8/34,416 (0.02%) alleles from individuals of Latino background (Lek et al., 2016). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the I647V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genome-Nilou Lab RCV002467810 SCV002764093 uncertain significance Amyotrophic lateral sclerosis type 5 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002467811 SCV002764094 uncertain significance Charcot-Marie-Tooth disease axonal type 2X criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000470611 SCV002764096 uncertain significance Hereditary spastic paraplegia 11 criteria provided, single submitter clinical testing
Ambry Genetics RCV004965466 SCV005504074 uncertain significance Inborn genetic diseases 2024-09-04 criteria provided, single submitter clinical testing The c.1939A>G (p.I647V) alteration is located in exon 10 (coding exon 10) of the SPG11 gene. This alteration results from a A to G substitution at nucleotide position 1939, causing the isoleucine (I) at amino acid position 647 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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