rs62508642

Positions:

• chr12-102877459-C-G

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3 PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: This c.441+3G>C (IVS4+3G>C) variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID:28982351, 5894915, 30050108). This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic PKU (PMID:30050108). This variant was documented 12 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID:26503515, 16256386, 23932990). This variant is absent from the population databases ExAC and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very strong, PM2, PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229546/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 splice_region, intron
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 1.83

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 Pathogenic. Variant got 6 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.
• 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.441+3G>C		splice_region_variant, intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.441+3G>C		splice_region_variant, intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.441+3G>C		splice_region_variant, intron_variant			XP_016874859.1
LOC124902999	XR_007063428.1	n.808-2420C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.441+3G>C		splice_region_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 15, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 18, 2019	This c.441+3G>C (IVS4+3G>C) variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108). This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic PKU (PMID: 30050108). This variant was documented 12 times in patients with PAH deficiency; DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 26503515, 16256386, 23932990). This variant is absent from the population databases ExAC and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very strong, PM2, PP4_moderate. -

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
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs62508642; hg19: chr12-103271237;