rs62508582

Positions:

• chr12-102844370-C-A
• chr12-102844370-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3 PP4 PM2 PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1031G>T (p.Gly344Val) variant in PAH has been reported in 2 siblings with classic PKU, detected with pathogenic variant p.R243Q. (PMID:10679941). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Ser and p.Gly344Arg are likely pathogenic by PAH VCEP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229290/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 O:1
• Conservation: PhyloP100: 7.91

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]

PAH (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• 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
PAH	NM_000277.3	c.1031G>T	p.Gly344Val	missense_variant	10/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1031G>T	p.Gly344Val	missense_variant	11/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1031G>T	p.Gly344Val	missense_variant	10/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 11, 2021	The c.1031G>T (p.Gly344Val) variant in PAH has been reported in 2 siblings with classic PKU, detected with pathogenic variant p.R243Q. (PMID: 10679941). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Other missense changes at the same amino acid residue have been seen before (p.Gly344Asp, p.Gly344Ser and p.Gly344Arg are likely pathogenic by PAH VCEP). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP3, PP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 24, 2018	- -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
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	0.87	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.9	H;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.7	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.99		Loss of ubiquitination at K341 (P = 0.0464);.;
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs62508582; hg19: chr12-103238148;