Submissions for variant NM_000277.3(PAH):c.653G>T (p.Gly218Val)

gnomAD frequency: 0.00001  dbSNP: rs62514933

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000705590	SCV002032210	pathogenic	Phenylketonuria	2020-07-09	reviewed by expert panel	curation	The c.653G>T (p.Gly218Val) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 8406445, 9781015, 10479481). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: p.R158Q, p.I65T (PMID: 10479481); p.Y414C (PMID: 8632937); c.1066-11G>A, p.Arg270Lys, (PMID: 26666653); p.P281L (PMID: 24368688); p.R408W (PMID: 11032331); p.S349P (PMID: 22841515); c.1223G > A (p.R408Q) (PMID: 29102225). It co-segregated with disease (PKU) in 2 sisters (PMID: 8831077). Computational prediction tools and conservation analysis support a deleterious effect on 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, PP1, PP3, PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705590	SCV000834592	pathogenic	Phenylketonuria	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 218 of the PAH protein (p.Gly218Val). This variant is present in population databases (rs62514933, gnomAD 0.004%). This missense change has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 8632937, 10479481, 12655546, 24368688, 26666653). ClinVar contains an entry for this variant (Variation ID: 102773). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000705590	SCV001338649	pathogenic	Phenylketonuria	2022-07-07	criteria provided, single submitter	clinical testing	Variant summary: PAH c.653G>T (p.Gly218Val) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251318 control chromosomes. c.653G>T has been reported in the literature in multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency, including hyperphenylalaninemia and mild-, moderate- and classic forms of phenylketonuria (e.g. Guldberg_1993, Benit_1999, Eisensmith_1996, Pey_2003, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant causes abnormal oligomerization (Pey_2003) resulting in decreased enzyme function, with about 15-25% residual activity (Benit_1999, Himmelreich_2018). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000705590	SCV002779484	pathogenic	Phenylketonuria	2021-11-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000705590	SCV004209563	pathogenic	Phenylketonuria	2023-10-02	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV000705590	SCV005043025	pathogenic	Phenylketonuria	2024-04-25	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2, PP3, PS3, PM3, PP5; Variant was found in heterozygous state
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089023	SCV000119628	not provided	not provided		no assertion provided	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000089023	SCV001552745	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The PAH p.Gly218Val variant was identified in the compound heterozygous state with another pathogenic PAH variant in 7 of 1806 proband chromosomes (frequency: 0.0039) from individuals or families with both mild and severe phenylkenoturia (PKU) and phenylalanine hydroxylase deficiency (Bénit_1999_PMID:10479481; Jeannesson-Thivisol_2015_PMID:26666653; Ho_2014_PMID:24368688; Güttler_1999_PMID:10429004; Desviat_1999_PMID:10234516). The variant was identified in dbSNP (ID: rs62514933) and ClinVar (classified as pathogenic for PKU by Invitae in 2018). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 4 of 282732 chromosomes at a frequency of 0.000014 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24974 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 129052 chromosomes (freq: 0.000023), but not in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Gly218 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Further, the p.G218V variant was found to have reduced protein stability and accelerated protein degradation (Pey_2003_PMID:12655546). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Natera, Inc.	RCV000705590	SCV002088651	pathogenic	Phenylketonuria	2020-12-04	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390791	SCV004118968	pathogenic	PAH-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The PAH c.653G>T variant is predicted to result in the amino acid substitution p.Gly218Val. This variant has previously been reported, along with a second causative PAH variant, in several patients with phenylalanine hydroxylase deficiency (Guldberg et al. 1993. PubMed ID: 8406445; Bénit et al. 1999. PubMed ID: 10479481; Pey et al. 2003. PubMed ID: 12655546; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). In functional studies, the p.Gly218Val variant has been shown to decrease the activity of the PAH protein, although the amount of residual enzyme activity reported has varied between studies (Bénit et al. 1999. PubMed ID: 10479481; Pey et al. 2003. PubMed ID: 12655546; Himmelreich et al. 2018. PubMed ID: 30037505). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. It is interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel, and as pathogenic or likely pathogenic by other submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/102773). Based on the collective evidence, this variant is interpreted as pathogenic.