ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.688G>A (p.Val230Ile) (rs62516152)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel, RCV000411829 SCV000852131 likely pathogenic Phenylketonuria 2018-08-12 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PP4_Moderate: V2301 seen in 1 patient with PAH deficiency. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_VeryStrong: Detected in trans with IVS 10-11G>A, L48S, R408W, E390G). Upgraded per ClinGen SVI Workgroup. (PMID:15943553; PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP4_Moderate, PM3_VeryStrong).
Counsyl RCV000411829 SCV000485287 likely pathogenic Phenylketonuria 2016-01-18 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000411829 SCV000745572 pathogenic Phenylketonuria 2016-01-18 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089035 SCV000119640 not provided not provided no assertion provided not provided
Fulgent Genetics,Fulgent Genetics RCV000411829 SCV000893947 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000089035 SCV000239065 likely pathogenic not provided 2019-04-02 criteria provided, single submitter clinical testing The V230I missense variant in the PAH gene has been reported previously in association with non-classic phenylketonuria (PKU) in patients with milder hyperphenylalaninemia (Guldberg et al., 1993 PAH Consortium database). Functional studies report the V230I variant is located in the catalytic domain and may be associated with tetrahydrobiopterin (BH 4 )-responsiveness in patients due to the residual enzyme activity of 63% (Zurfluh et al., 2007).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000411829 SCV000744097 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000411829 SCV000746354 likely pathogenic Phenylketonuria 2017-12-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000411829 SCV000696458 pathogenic Phenylketonuria 2016-03-03 criteria provided, single submitter clinical testing Variant summary: The c.688G>A in PAH gene is a missense variant that involves a conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the broad control population dataset of ExAC at a low frequency (0.042%), which does not exceed the maximum frequency for a pathogenic variant in PAH gene (0.79%). The variant has been reported in multiple pts presented with mild hyperphenylalaninemia or mild PKU with the remaining enzymatic activity being about 63% of normal. In general, patients with mild hyperphenylalaninemia do not require restrictive diet or supplementary treatment unless Phe concentrations reach the clinical threshold. Taken together, the variant was classified as Pathogenic for Mild Hyperphenylalaninemia.
Invitae RCV000411829 SCV000629205 pathogenic Phenylketonuria 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 230 of the PAH protein (p.Val230Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs62516152, ExAC 0.2%). This variant has been reported in the literature in multiple individuals affected with hyperphenilalanemia (HPA) or mild phenylketonuria (PKU) both as a heterozygous in combination with other PAH variant, or as a homozygous (PMID: 8268925, 25087612, 23500595, 17935162, 17096675, 24048906, 10598814, 18299955, 23792259, Invitae). ClinVar contains an entry for this variant (Variation ID: 102784). Experimental studies have shown that this missense change has a mild effect on protein structure and folding in vitro (PMID: 11161839). For these reasons, this variant has been classified as Pathogenic.

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