Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000993633 | SCV001146765 | pathogenic | Phenylketonuria | 2019-04-04 | reviewed by expert panel | curation | The c.266_267insG variant in PAH has been previously reported as a homozygous variant in an Australian proband with PKU (not otherwise specified) from a consanguineous family; the paper does not state whether BH4 deficiency was excluded (PMID: 24368688). The variant was also found in a French proband with classic PKU in trans with the p.Pro281Leu variant, which has been classified as a VUS per internal PAH ClinGen Working Group classification (see PAH0660); the paper does not state whether BH4 deficiency was excluded (PMID: 26666653). The variant was also found in 1 Caucasian proband with classic PKU, in trans with the known pathogenic c.1066-11G>A variant (PMID: 23430918); BH4 deficiency was excluded via biochemical testing per the recruiting study protocol (PMID: 17846916). Finally, it was found in three Southern German probands with classic PKU; no further details regarding genotype and/or exclusion of BH4 deficiency were given (PMID: 12655553). Thus, PP4_Moderate and PM3 apply per the report in PMID: 17846916. The sequence change results in a frameshift variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate. |