rs62508694

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3PS3_SupportingPM2PP3PP4

This summary comes from the ClinGen Evidence Repository: The c.733G>C (p.Val245Leu) variant in PAH has been reported in 3 individuals with PAH deficiency, detected with pathogenic variants p.R408Q and p.A104D (PMID:8659548, 24368688). This variant has an extremely low allele frequency (0.000008972) in gnomAD. This variant has 13% enzyme activity (PMID:11161839). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PS3, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229724/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

PAH
ENST00000553106.6 missense

Scores

13
5
1

Clinical Significance

Pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 7 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAHNM_000277.3 linkuse as main transcriptc.733G>C p.Val245Leu missense_variant 7/13 ENST00000553106.6 NP_000268.1
PAHNM_001354304.2 linkuse as main transcriptc.733G>C p.Val245Leu missense_variant 8/14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.733G>C p.Val245Leu missense_variant 7/131 NM_000277.3 ENSP00000448059 P1
PAHENST00000307000.7 linkuse as main transcriptc.718G>C p.Val240Leu missense_variant 8/145 ENSP00000303500
PAHENST00000549247.6 linkuse as main transcriptn.492G>C non_coding_transcript_exon_variant 1/62

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251200
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135752
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1461854
Hom.:
0
Cov.:
32
AF XY:
0.0000371
AC XY:
27
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 03, 2022Variant summary: PAH c.733G>C (p.Val245Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain 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 4e-06 in 251200 control chromosomes. c.733G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Guldberg_1996, Quirk_2012, Tyfield_1997, Ho_2014, Grange_2014). 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 PAH enzyme activity. Four 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 (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 18, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingCounsylJan 19, 2018- -
Pathogenic, reviewed by expert panelcurationClinGen PAH Variant Curation Expert PanelJun 26, 2020The c.733G>C (p.Val245Leu) variant in PAH has been reported in 3 individuals with PAH deficiency, detected with pathogenic variants p.R408Q and p.A104D (PMID: 8659548, 24368688). This variant has an extremely low allele frequency (0.000008972) in gnomAD. This variant has 13% enzyme activity (PMID: 11161839). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PS3, PM2, PM3, PP3. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 14, 2023This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 245 of the PAH protein (p.Val245Leu). This variant is present in population databases (rs62508694, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8659548, 22841515, 24368688, 24667082). ClinVar contains an entry for this variant (Variation ID: 102810). 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 expected to disrupt PAH protein function. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 17924342). This variant disrupts the p.Val245 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8088845, 24296287, 25596310, 26803807). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 08, 2016- -
not provided, no classification providedliterature onlyDeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 13, 2022Functional analysis found that V245L is associated with 7-15% enzyme activity compared to wild-type and is associated with a classic PKU phenotype (Gjetting et al., 2001; Pey et al., 2007).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9012412, 8659548, 25596310, 11161839, 24368688, 22841515, 17924342, 24667082, 24296287, 8088845, 35339094, 26803807) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
1.0
D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Pathogenic
4.8
H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.86
MutPred
0.97
Loss of methylation at R243 (P = 0.1487);.;
MVP
0.96
MPC
0.24
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62508694; hg19: chr12-103246702; API