ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.926C>T (p.Ala309Val) (rs62642935)

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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, RCV000150082 SCV000852158 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Low frequency. 1.0e-5; PP3: All databases agree on damaging effect. REVEL=0.921; PS3: Enzyme activity = 30% (Ho, 2008) (PMID:18590700); PM3: Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T (PMID:26666653); PP4: Single patient with classic PKU (>1200umol/L), BH4 defect not excluded (PMID:26666653). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4).
Counsyl RCV000150082 SCV000487182 likely pathogenic Phenylketonuria 2016-10-20 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078538 SCV000119775 not provided not provided no assertion provided not provided
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078538 SCV000110394 pathogenic not provided 2012-08-07 criteria provided, single submitter clinical testing
GeneDx RCV000078538 SCV000581842 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing The A309V variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium Database. The A309V variant has most often been reported in association with amild-moderate phenylketonuria (PKU) phenotype (Guldberg et al., 1993; Pey et al., 2003; Aldámiz-Echevarría et al., 2016); however, it has also been identified in an individual with a classic PKUphenotype (Couce et al., 2013). Therefore, genotype/phenotype predictions for the A309V variantcannot be made at this time. Functional analysis of A309V found that it is associated with 44-70%residual enzyme activity compared to wild type (Pey et al., 2003; Zurfluh et al. 2008). The A309Vvariant is classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008; Aldámiz-Echevarría et al., 2016). We interpret A309V as pathogenic.
Invitae RCV000150082 SCV000629226 pathogenic Phenylketonuria 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 309 of the PAH protein (p.Ala309Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs62642935, ExAC 0.001%). This variant has been reported in the literature in multiple individuals affected with PKU in the homozygous state and in the compound heterozygous state in combination with other pathogenic PAH variants (PMID: 12655546, 21871829, 26666653, 27121329). ClinVar contains an entry for this variant (Variation ID: 92753). Experimental studies have shown that this missense change causes reduced PAH enzymatic activity, folding defects, and lower affinity to phenylalanine and BH4 (PMID: 15459954, 16504182, 12655546). For these reasons, this variant has been classified as Pathogenic.

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