rs62642929
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4
The NM_000277.3(PAH):c.311C>A(p.Ala104Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A104V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.311C>A | p.Ala104Asp | missense_variant | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9922G>T | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.311C>A | p.Ala104Asp | missense_variant | 4/14 | ||
PAH | XM_017019370.2 | c.311C>A | p.Ala104Asp | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.311C>A | p.Ala104Asp | missense_variant | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251446Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135886
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461832Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727222
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74310
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 27, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 104 of the PAH protein (p.Ala104Asp). This variant is present in population databases (rs62642929, gnomAD 0.009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18299955, 22112818, 22526846, 23764561, 26666653). ClinVar contains an entry for this variant (Variation ID: 102650). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 15, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 21, 2017 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 07, 2018 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 11, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 06, 2023 | - - |
not provided Pathogenic:4Other:1
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | 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); Published functional studies demonstrate a damaging effect: reduced protein expression and catalytic activity (Waters et al., 1997; Shi et al., 2012); Associated with tetrahydrobiopterin (BH4) responsiveness (Zurfluh et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11461190, 10384369, 9792411, 22526846, 21953985, 9429153, 24368688, 17627389, 23357515, 12655551, 1301187, 30037505, 30648773, 31355225, 22112818, 18299955, 23764561, 26666653, 26542770, 23514811, 32668217, 33101986, 32778825, 9191407, 17935162) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 07, 2016 | - - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
PAH-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2024 | The PAH c.311C>A variant is predicted to result in the amino acid substitution p.Ala104Asp. This variant has been reported in the homozygous state or with a second PAH variant in patients with phenylalanine hydroxylase deficiency, ranging from mild hyperphenylalaninemia to classic phenylketonuria (PKU) (e.g., Zekanowski et al. 1997. PubMed ID: 9429153; Bercovich et al. 2008. PubMed ID: 18299955; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Trunzo et al. 2015. PubMed ID: 26210745; Su et al. 2019. PubMed ID: 31355225; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). Based on functional studies, the p.Ala104Asp amino acid change has been reported to result in reduced PAH enzyme activity and has been classified as a BH4-responsive amino acid substitution (Zurflüh et al. 2008. PubMed ID: 17935162; Shi et al. 2012. PubMed ID: 21953985; Himmelreich et al. 2018. PubMed ID: 30037505). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD. It has been classified as pathogenic by multiple outside laboratories as well as the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/102650/). Based on these observations, we classify this variant as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at