ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.168G>T (p.Glu56Asp)

dbSNP: rs199475567
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001543635 SCV001762302 pathogenic Phenylketonuria 2020-06-29 reviewed by expert panel curation The c.168G>T (p.Glu56Asp) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID: 21147011, 23932990, 30050108). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID: 8019568); R408W and T356X (PMID: 21147011); p.V399V, c.442-1G>A, p.I65T, p.R261Q (PMID: 30050108). Computational prediction tools and conservation analysis do not agree on the impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp RCV001543635 SCV004296194 pathogenic Phenylketonuria 2023-02-01 criteria provided, single submitter clinical testing An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 56 of the PAH protein (p.Glu56Asp). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217). ClinVar contains an entry for this variant (Variation ID: 102610).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088852 SCV000119447 not provided not provided no assertion provided not provided

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