Submissions for variant NM_000277.3(PAH):c.30C>G (p.Gly10=)

gnomAD frequency: 0.00069  dbSNP: rs1801145

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779088	SCV000915573	uncertain significance	Phenylketonuria	2017-08-23	criteria provided, single submitter	clinical testing	The PAH gene is the only gene in which variants are known to cause phenylalanine hydroxylase deficiency. The PAH c.30C>G (p.Gly10=) synonymous variant has been reported in one study and found in a compound heterozygous state with an indel variant in one family with two affected siblings. The authors suggest that the c.30C>G variant may cause aberrant mRNA splicing. They observed an increase in binding of c.30C>G PAH RNA to heterogeneous nuclear ribonucleoprotein (hnRNP) proteins which inhibit splicing (Dobrowlski et al. 2010). The p.Gly10 variant was absent from 200 control individuals and is reported at a frequency of 0.00330 in the Other population of the Exome Aggregation Consortium. Based on the evidence, the p.Gly10 variant is classified as a variant of unknown significance but suspicious for pathogenicity for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779088	SCV001418959	uncertain significance	Phenylketonuria	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change affects codon 10 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs1801145, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with phenylketonuria (PKU) (PMID: 2018035, 20457534). ClinVar contains an entry for this variant (Variation ID: 102649). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 20457534). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844038	SCV002103436	uncertain significance	not specified	2024-12-02	criteria provided, single submitter	clinical testing	Variant summary: PAH c.30C>G results in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00064 in 251468 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00064 vs 0.0079), allowing no conclusion about variant significance. c.30C>G was initially described in a family with three siblings who presented with different clinical manifestations of Hyperphenylalaninemia ranging from "normal" (Sibling A) to severe retardation (Sibling B) and dietarily responsive (Sibling C) (DiSilvestre_1991). As this study predated PAH gene sequencing, the exact variation was not specified. In a subsequent report, two of these three siblings were reported as harboring this variant but their exact identity relative to the previously published report was not specified (example, Dobrowolski_2010). These reports do not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 2018035, 20457534). ClinVar contains an entry for this variant (Variation ID: 102649). Based on the evidence outlined above, the variant was classified as uncertain significance.
Centogene AG - the Rare Disease Company	RCV000779088	SCV002598523	uncertain significance	Phenylketonuria	2019-07-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321585	SCV002608390	uncertain significance	Inborn genetic diseases	2024-02-17	criteria provided, single submitter	clinical testing	The c.30C>G (p.G10G) alteration is located in exon 1 (coding exon 1) of the PAH gene. This alteration consists of a C to G substitution at nucleotide position 30. This nucleotide substitution does not change the amino acid at codon 10. However, this change occurs in the last nucleotide of Exon 1 (c.-472_60) which makes it likely to have some effect on normal mRNA splicing. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000088895	SCV002757084	uncertain significance	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Has not been previously published in an individual with PAH-related phenylketonuria as pathogenic or benign to our knowledge; Some evidence indicates the variant may cause aberrant splicing but the effect needs to be further confirmed; This variant is associated with the following publications: (PMID: 34426522, 20457534, 2018035, 29473999, 25087612)
Revvity Omics, Revvity	RCV000779088	SCV003816610	uncertain significance	Phenylketonuria	2021-09-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000779088	SCV004209619	uncertain significance	Phenylketonuria	2023-08-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000088895	SCV004698320	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PAH: BP4, BP7
Breakthrough Genomics, Breakthrough Genomics	RCV000088895	SCV005191952	uncertain significance	not provided		criteria provided, single submitter	not provided
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088895	SCV000119493	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000779088	SCV002088681	uncertain significance	Phenylketonuria	2019-12-27	no assertion criteria provided	clinical testing