ClinVar Miner

Submissions for variant NM_022041.3(GAN):c.944C>T (p.Pro315Leu) (rs144486241)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236891 SCV000293006 likely pathogenic not provided 2018-02-15 criteria provided, single submitter clinical testing The P315L variant in the GAN gene has been reported previously in trans with a second GAN variant in two unrelated individuals with giant axonal neuropathy (Bruno et al., 2004; Houlden et al., 2007). The P315L variant is observed in 6/6,614 (0.09%) alleles from individuals of Finnish background, including one homozygous individual, in large population cohorts (Lek et al., 2016). The P315L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. We interpret P315L as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000396992 SCV000399018 uncertain significance Giant axonal neuropathy 1 2017-04-27 criteria provided, single submitter clinical testing The GAN c.944C>T (p.Pro315Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two patients with giant axonal neuropathy, one with a missense variant on the second allele, and one with a frameshift variant (Bruno et al. 2004; Houlden et al. 2007). The p.Pro315Leu variant was also found in a heterozygous state in one of the parents diagnosed with mild multiple sclerosis. The p.Pro315Leu variant was absent from 100 controls but is reported at a frequency of 0.000907 in the European (Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Pro315Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for giant axonal neuropathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000396992 SCV000812327 uncertain significance Giant axonal neuropathy 1 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 315 of the GAN protein (p.Pro315Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs144486241, ExAC 0.09%), including at least one homozygous and/or hemizygous individual. This variant has been reported in combination with other GAN variants in individuals affected with giant axonal neuropathy (PMID:14718689, 17578852). ClinVar contains an entry for this variant (Variation ID: 245843). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; 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.

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