Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV001093705 | SCV002548646 | pathogenic | Hyperphenylalaninemia due to DNAJC12 deficiency | 2021-07-22 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002554809 | SCV003276366 | pathogenic | not provided | 2024-01-02 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp175*) in the DNAJC12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the DNAJC12 protein. This variant is present in population databases (rs370032864, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with hyperphenylalaninemia (PMID: 30626930, 32333439). ClinVar contains an entry for this variant (Variation ID: 870655). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DNAJC12 function (PMID: 32333439). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002555938 | SCV003661700 | pathogenic | Inborn genetic diseases | 2021-07-30 | criteria provided, single submitter | clinical testing | The c.524G>A (p.W175*) alteration, located in exon 5 (coding exon 5) of the DNAJC12 gene, consists of a G to A substitution at nucleotide position 524. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 175. This alteration occurs at the 3' terminus of the DNAJC12 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12.2% (24/198 amino acids) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been detected in the homozygous and compound heterozygous states in multiple individuals with hyperphenylalaninemia (HPA) (Gallego, 2020). Functional studies on fibroblasts showed reduced amounts of PAH and PAH activity affecting the PAH folding process. Steady-state tyrosine hydroxylase levels were also reduced while tryptophan hydroxylase 2 levels were not affected (Gallego, 2020). Based on the available evidence, this alteration is classified as pathogenic. |
| Baylor Genetics | RCV001093705 | SCV003835602 | pathogenic | Hyperphenylalaninemia due to DNAJC12 deficiency | 2022-04-14 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV003396740 | SCV004104288 | pathogenic | DNAJC12-related condition | 2023-06-13 | criteria provided, single submitter | clinical testing | The DNAJC12 c.524G>A variant is predicted to result in premature protein termination (p.Trp175*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with hyperphenylalaninaemia (Navarrete et al 2019. PubMed ID: 30626930; Gallego D et al 2020. PubMed ID: 32333439). This variant is reported in 0.093% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-69556947-C-T). Nonsense variants in DNAJC12 are expected to be pathogenic. This variant is interpreted as pathogenic. |
| Centro de Biología Molecular Severo Ochoa, |
RCV001093705 | SCV001245613 | pathogenic | Hyperphenylalaninemia due to DNAJC12 deficiency | 2020-02-12 | no assertion criteria provided | research |