ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.676C>A (p.Gln226Lys)

dbSNP: rs62508696
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001199975 SCV001370797 likely pathogenic Phenylketonuria 2020-03-14 reviewed by expert panel curation The c.676C>A (p.Gln226Lys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID 26481238, 29654578). This variant is absent in population databases. This variant was detected in trans with pathogenic variants p.Gln20* and p.Ile306Val. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.
3billion RCV001199975 SCV002058443 pathogenic Phenylketonuria 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000932251, PMID:26481238, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 26481238, 29654578, PM3_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 29654578, PS3_S). A different missense change at the same codon has been reported to be associated with PAH related disorder (PMID:11678552, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.868, 3CNET: 0.989, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria; PKU (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.

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