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rs62508588

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000277.3(PAH):c.728G>T(p.Arg243Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PAH
NM_000277.3 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic reviewed by expert panel P:1O: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 18 ACMG points.

PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-102852929-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 12-102852929-C-A is Pathogenic according to our data. Variant chr12-102852929-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102808.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102852929-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAHNM_000277.3 linkuse as main transcriptc.728G>T p.Arg243Leu missense_variant 7/13 ENST00000553106.6
PAHNM_001354304.2 linkuse as main transcriptc.728G>T p.Arg243Leu missense_variant 8/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.728G>T p.Arg243Leu missense_variant 7/131 NM_000277.3 P1
PAHENST00000307000.7 linkuse as main transcriptc.713G>T p.Arg238Leu missense_variant 8/145
PAHENST00000549247.6 linkuse as main transcriptn.487G>T non_coding_transcript_exon_variant 1/62

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Phenylketonuria Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen PAH Variant Curation Expert PanelFeb 14, 2021The c.728G>T (p.Arg243Leu) variant in PAH has been reported in 1 individual with PKU detected with pathogenic variant p.R261Q (P 9 submitters) PMID: 12655553, 20217238. This variant is absent in population databases. Computational evidence supports a deleterious effect. Another missense change at the same amino acid,p .Arg243Gln, is pathogenic in ClinVar by multiple submitters (variation ID 591). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PM5, PP3. -
not provided Other:1
not provided, no classification providedliterature onlyDeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
31
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;D
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
3.6
H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-6.7
D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.95
MutPred
0.95
Loss of methylation at R243 (P = 0.0151);.;
MVP
0.98
MPC
0.26
ClinPred
1.0
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs62508588; hg19: chr12-103246707; API