rs62508588

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3_SupportingPP3PP4PM5PM2

This summary comes from the ClinGen Evidence Repository: The 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229719/MONDO:0009861/006

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PM5
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.728G>T p.Arg243Leu missense_variant 7/13 ENST00000553106.6 NP_000268.1
PAHNM_001354304.2 linkuse as main transcriptc.728G>T p.Arg243Leu 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.728G>T p.Arg243Leu missense_variant 7/131 NM_000277.3 ENSP00000448059 P1
PAHENST00000307000.7 linkuse as main transcriptc.713G>T p.Arg238Leu missense_variant 8/145 ENSP00000303500
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