Submissions for variant NM_018972.4(GDAP1):c.89A>T (p.His30Leu)

dbSNP: rs896431562

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482807	SCV000565033	likely pathogenic	not provided	2014-06-16	criteria provided, single submitter	clinical testing	The H30L variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The H30L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. A mutation in a nearby residue (S34C) has been reported in the Human Gene Mutation Database in association with CMT disease (Stenson et al., 2009), supporting the functional importance of this region of the protein. Most in silico programs predict this variant to be damaging to the protein structure/function. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525760	SCV003276149	uncertain significance	Charcot-Marie-Tooth disease type 4A	2022-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 30 of the GDAP1 protein (p.His30Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GDAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 418229). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GDAP1 protein function. 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.
3billion	RCV002525760	SCV005905347	uncertain significance	Charcot-Marie-Tooth disease type 4A	2023-06-20	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.48; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GDAP1 related disorder (ClinVar ID: VCV000418229). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.