rs62508718

Positions:

• chr12-102855193-A-C
• chr12-102855193-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3_Strong PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.649T>G (p.Cys217Gly) variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded). This variant is absent in population databases. This variant was detected with pathogenic variants: p.P281L (PMID:8807319), IVS10-11G>A, and p.V245A (PMID:27121329). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229673/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.649T>G	p.Cys217Gly	missense_variant	6/13	ENST00000553106.6
PAH	NM_001354304.2	c.649T>G	p.Cys217Gly	missense_variant	7/14
PAH	XM_017019370.2	c.649T>G	p.Cys217Gly	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.649T>G	p.Cys217Gly	missense_variant	6/13	1	NM_000277.3	P1
PAH	ENST00000549111.5	n.745T>G		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.634T>G	p.Cys212Gly	missense_variant	7/14	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Jul 06, 2020

The c.649T>G (p.Cys217Gly) variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded). This variant is absent in population databases. This variant was detected with pathogenic variants: p.P281L (PMID: 8807319), IVS10-11G>A, and p.V245A (PMID: 27121329). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-12	D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.067	T;T
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.93		Gain of disorder (P = 0.0308);.;
MVP		1.0
MPC		0.26
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.98

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

Other links and lift over

dbSNP: rs62508718; hg19: chr12-103248971;