ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.716G>T (p.Gly239Val)

gnomAD frequency: 0.00001  dbSNP: rs62507283
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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 RCV001215843 SCV001572848 likely pathogenic Phenylketonuria 2020-10-23 reviewed by expert panel curation The c.716G>T (p.Gly239Val) variant in PAH has been reported in 2 individuals with classic PKU (PMID 10394930, 31623983) detected with pathogenic variants p.R408W and IVS10–11g>a (PMID: 32106880). This variant has extremely low frequency in gnomAD (MAF=0.00006). 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, PM2, PM3, PP3.
Eurofins Ntd Llc (ga) RCV000089051 SCV000203184 uncertain significance not provided 2015-09-29 criteria provided, single submitter clinical testing
Invitae RCV001215843 SCV001387607 pathogenic Phenylketonuria 2023-09-27 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 102800). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This variant disrupts the p.Gly239 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 7833954, 29499199; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with PAH-related conditions (PMID: 23357515; Invitae). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 239 of the PAH protein (p.Gly239Val). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001215843 SCV003928908 pathogenic Phenylketonuria 2023-04-26 criteria provided, single submitter clinical testing Variant summary: PAH c.716G>T (p.Gly239Val) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250956 control chromosomes (gnomAD). c.716G>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Zschocke_1999, Sarkissian_2011, Sterl_2013, Reblova_2013, Rajabi_2019, Hillert_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, several other missense changes affecting the same amino acid (G239A/D/S) are reported in affected individuals (HGMD), supporting the clinical importance of this residue. The following publications have been ascertained in the context of this evaluation (PMID: 10394930, 23430918, 22526846, 23357515, 31623983, 32668217). Three submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1), likely pathogenic (n=1; i.e. the expert panel), or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001215843 SCV004209602 likely pathogenic Phenylketonuria 2023-08-31 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089051 SCV000119656 not provided not provided no assertion provided not provided

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