ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.692C>T (p.Pro231Leu) (rs121908114)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000214299 SCV000613472 pathogenic not provided 2017-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000214299 SCV000279443 likely pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing A P231L variant that is likely pathogenic has been identified in the GDAP1 gene. The P231L variant has been previously reported as a homozygous variant in three siblings with CMT; heterozygous carriers of the variant were reported to be unaffected (Xin et al., 2008). Additionally, the P231L variant has been observed in the homozygous state in multiple individuals affected with CMT who were tested at GeneDx. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMT neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. The P231L variant is observed in 6/34372 (0.02%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000703370 SCV000832267 uncertain significance Charcot-Marie-Tooth disease, type 4A 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 231 of the GDAP1 protein (p.Pro231Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to segregate with Charcot–Marie–Tooth disease in a family with 3 affected individuals (PMID: 18492089). ClinVar contains an entry for this variant (Variation ID: 4202). 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: "Probably 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.
OMIM RCV000004422 SCV000024595 pathogenic Charcot-Marie-Tooth disease type 2K 2008-09-01 no assertion criteria provided literature only

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