ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.618C>A (p.Tyr206Ter)

dbSNP: rs62517201
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000672692 SCV004222619 pathogenic Phenylketonuria 2023-10-13 reviewed by expert panel curation The c.618C>A (p.Tyr206Ter) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in 4 patients with classic PKU with known pathogenic variants: c.611A>G (PMID: 16256386); p.Arg241Cys (PMID:25456745); and c.1197A>T p.Val399Val (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.00005). In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PM3_strong, PP4, PVS1.
Counsyl RCV000672692 SCV000797826 pathogenic Phenylketonuria 2018-02-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000672692 SCV000919907 pathogenic Phenylketonuria 2017-09-08 criteria provided, single submitter clinical testing Variant summary: The PAH c.618C>A (p.Tyr206X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.727C>T, p.Arg243X; c.1055delG, p.Gly352fsX48; c.1089delG, p.Lys363fsX37). One in silico tool predicts a damaging outcome for this variant. One functional study confirmed that the variant leads to a nonsense mutation that caused significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay (Bashyam 2014). This variant was found in 1/121330 control chromosomes at a frequency of 0.00082%, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.79057%). The variant was reported in the literature in multiple patients with PKU (Song 2006, Bashyam 2014, Li 2015, Acosta 2001). Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000672692 SCV000946663 pathogenic Phenylketonuria 2023-10-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr206*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62517201, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 16256386, 24130151, 27121329). ClinVar contains an entry for this variant (Variation ID: 556660). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000672692 SCV004209586 pathogenic Phenylketonuria 2023-11-06 criteria provided, single submitter clinical testing
Natera, Inc. RCV000672692 SCV001453118 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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