ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Athena Diagnostics Inc RCV000214299 SCV000613472 pathogenic not provided 2021-03-05 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity ( This variant segregates with disease in at least one family. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Invitae RCV000703370 SCV000832267 pathogenic Charcot-Marie-Tooth disease, type 4A 2020-09-20 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 observed to segregate with autosomal recessive Charcot-Marie-Tooth disease in a family (PMID: 18492089) and has been observed in the homozygous state in individuals affected with Charcot-Marie-Tooth disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 4202). 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: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004422 SCV000024595 pathogenic Charcot-Marie-Tooth disease axonal type 2K 2008-09-01 no assertion criteria provided literature only
Genesis Genome Database RCV000857208 SCV000999790 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research
Inherited Neuropathy Consortium RCV000857208 SCV001190052 likely pathogenic Charcot-Marie-Tooth disease no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.