ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.311C>A (p.Ala104Asp) (rs62642929)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000349567 SCV000852162 pathogenic Phenylketonuria 2018-08-07 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency: 0.00009 in gnomAD; PS3: 26% PAH enzyme activity; PM3_Strong: Detected with Y414C, pathogenic in ClinVar and V245L (P/LP) (PMID:9429153; PMID:24368688). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PS3, PM3_Strong).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088896 SCV000330985 pathogenic not provided 2016-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000088896 SCV000617703 pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing The A104D variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium Database. The A104D variant has been reported previously in the heterozygous state, in the presence of a second PAH variant, in association with phenylketonuria (PKU) (Eisensmith et al., 1992; Zekanowski et al., 1997; Pronina et al., 2003; Wang et al., 2007; Ho et al., 2014). The A104D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A104D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Alanine are tolerated across species. In vitro functional studies demonstrated the A104D mutant protein exhibited reduced enzyme activity as compared to the wild type protein (Shi et al., 2012). We interpret A104D as a pathogenic variant.
Invitae RCV000349567 SCV000830766 pathogenic Phenylketonuria 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 104 of the PAH protein (p.Ala104Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs62642929, ExAC 0.006%). This variant has been observed in combination with another PAH variant in individuals affected with phenylketonuria (PMID: 22526846, 22112818, 18299955, 23764561, 26666653). ClinVar contains an entry for this variant (Variation ID: 102650). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change has a modest effect on oligomerization in a yeast two hybrid system (PMID: 11461190). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000349567 SCV000914557 pathogenic Phenylketonuria 2019-01-11 criteria provided, single submitter clinical testing Across a selection of the available literature, the PAH c.311C>A (p.Ala104Asp) missense variant has been identified in at least 12 individuals with phenylalanine hydroxylase deficiency (PAH), including in one in a homozygous state, and in 11 in a compound heterozygous state (Guldberg et al. 1995; Zekanowski et al. 1997; Pronina et al. 2003; Ho et al. 2014; Trunzo et al. 2015). The p.Ala104Asp variant is associated with a mild phenotype with the exception of one compound heterozygous individual who presented with the classical form. Control data are unavailable for this variant, which is reported at a frequency of 0.000089 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrated that the p.Ala104Asp PAH retained 26% of its activity but with a significantly reduced half-life of the aggregates compared to wild type PAH. In vitro, wild type PAH was comprised of tetramers and dimers, whereas mutant PAH was primarily dimeric with moderate amounts of aggregates, and significantly reduced amounts of tetramers (Waters et al. 1998). Additionally, hybrid expression models have shown a modest decrease in reporter activity as well as an increase in the rate of degradation in homomeric interactions for the p.Ala104Asp mutant as compared to wildtype (Waters et al. 2001). Based on the collective evidence, the p.Ala104Asp variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000349567 SCV000919919 pathogenic Phenylketonuria 2018-08-27 criteria provided, single submitter clinical testing Variant summary: PAH c.311C>A (p.Ala104Asp) results in a non-conservative amino acid change located in the ACT domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246214 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.3e-05 vs 0.0079), allowing no conclusion about variant significance. c.311C>A has been reported in the literature in multiple individuals affected with mild PKU due to Phenylalanine Hydroxylase Deficiency (mild Phenylketonuria)(Zurfluh_2008, Bayat_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088896 SCV000119494 not provided not provided no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.