ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect with significantly altered distribution of the ALDH18A1 protein within the mitochondrial network and reduced enzyme activity (Fischer-Zirnsak et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26320891)

This variant was identified as de novo (maternity and paternity confirmed).

The variantwas confirmed as de novo by parental testing. The same variant was also reported as de novo in one or more affected individuals with a consistent phenotype from multiple, unrelated families (PMID: 26320891) (PS2_VS). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217259, PMID:26320891, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000217261, PMID:26320891,26320891, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.821, 3CNET: 0.985, PP3_P). A missense variant is a common mechanism associated with Cutis laxa (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

A heterozygous missense variant was identified, NM_002860.3(ALDH18A1):c.412C>T in exon 4 of 18 of the ALDH18A1 gene (NB: This variant is non-coding in an alternative transcript). This substitution is predicted to create a major amino acid change from arginine to tryptophan at position 138 of the protein, NP_002851.2(ALDH18A1):p.Arg138Trp. The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the ϒ-glutamyl kinase domain (Fischer-Zirnsak, B. et al. (2015). In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is not present in the gnomAD population database. The variant has been previously reported as pathogenic in patients with cutis laxia (ClinVar, Fischer-Zirnsak, B. et al. (2015)). In addition, functional studies show that this variant causes altered sub-mitochondrial distribution and reduced enzymatic activity (Fischer-Zirnsak, B. et al. (2015)). Two different variants in the same codon resulting in changes to glutamine and leucine have also been reported as pathogenic in patients with cutis laxia (ClinVar, Fischer-Zirnsak, B. et al. (2015)). Analysis of parental samples indicated that this variant is de novo. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.