ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.611A>G (p.Tyr204Cys) (rs62514927)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000089007 SCV000329866 pathogenic not provided 2017-07-20 criteria provided, single submitter clinical testing The c.611 A>G variant in the PAH is a common pathogenic variant in Chinese patients with phenylketonuria (PKU) and is associated with a classic PKU phenotype (Lee et al., 2004; Yu et al., 2008; Chen et al., 2015). Functional analysis of c.611 A>G found that results in abnormal splicing and it is classified as a not responsive to tetrahydrobiopterin (BH4) therapy (Ellingsen et al., 1997; Sarkissian et al., 2012))
Fulgent Genetics,Fulgent Genetics RCV000000621 SCV000893948 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000621 SCV000917932 pathogenic Phenylketonuria 2018-12-13 criteria provided, single submitter clinical testing Variant summary: PAH c.611A>G (p.Tyr204Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. One publication reports experimental evidence showing that this variant affects mRNA splicing resulting in a 32-amino acid deletion in the core region of the PAH enzyme (Ellingsen_1997). The variant allele was found at a frequency of 1.2e-05 in 246108 control chromosomes (gnomAD). The variant, c.611A>G, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tao_2015, Liang_2014, Song_2005, Ellingsen_1997). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000000621 SCV000950704 pathogenic Phenylketonuria 2019-05-15 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 204 of the PAH protein (p.Tyr204Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs62514927, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 18985011, 15503242, 25894915), and has been shown on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (PMID: 2071149). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as EX6-96A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 590). Experimental studies have shown that this missense change disrupts PAH mRNA splicing (PMID: 8990021). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000000621 SCV001163722 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
OMIM RCV000000621 SCV000020771 pathogenic Phenylketonuria 1992-05-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089007 SCV000119611 not provided not provided no assertion provided not provided
Counsyl RCV000000621 SCV000220596 pathogenic Phenylketonuria 2018-10-22 no assertion criteria provided clinical testing

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