ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 647 of the GLDC protein (p.Pro647Leu). This variant is present in population databases (rs201135624, gnomAD 0.01%). This missense change has been observed in individual(s) with Smith-Magenis like phenotype (PMID: 27799067). ClinVar contains an entry for this variant (Variation ID: 254211). 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 GLDC 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.

Observed with a variant on the opposite allele (in trans) in a patient with intellectual disability, dysmorphic features, and epilepsy who also had a variant in another gene that may be responsible for the phenotype (Loviglio et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27799067)

Variant summary: GLDC c.1940C>T (p.Pro647Leu) results in a non-conservative amino acid change located in the Aromatic amino acid beta-eliminating lyase/threonine aldolase (IPR001597) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251462 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1940C>T has been reported in the literature in individuals affected with a Smith-Magenis syndrome-like phenotype (Loviglio_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27799067). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

The c.1940C>T (p.P647L) alteration is located in exon 17 (coding exon 17) of the GLDC gene. This alteration results from a C to T substitution at nucleotide position 1940, causing the proline (P) at amino acid position 647 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.