rs786204457

Positions:

• chr12-102912790-CC-TT

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4 PM3_Strong PVS1_Moderate PM2

This summary comes from the ClinGen Evidence Repository: The c.168_168+1delGGinsAA variant has been identified in at least 6 probands with classic PKU (PMIDs: 1301942, 8825928). It has been detected in the homozygous form (PMID:1301942) as well as in trans with the pathogenic variant R408W (PMID:8825928). This variant is absent from 1000G, ESP, and gnomAD databases. This variant results in a broken donor splice site, expected to result in the in-frame deletion of exon 2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PVS1_Moderate, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273936/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_donor, splice_region, synonymous, intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 5.03

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 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• 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.168_168+1delGGinsAA	p.57	splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.168_168+1delGGinsAA	p.57	splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.168_168+1delGGinsAA	p.57	splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.168_168+1delGGinsAA	p.57	splice_donor_variant, splice_region_variant, synonymous_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:5

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 29, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 23, 2023	ClinVar contains an entry for this variant (Variation ID: 188771). This variant results in the deletion of part of exon 2 (c.168_168+1delinsAA) of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individuals with phenylketonuria (PMID: 1301942, 8825928). This variant is also known as IVS2nt1. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 25, 2019	The c.168_168+1delGGinsAA variant has been identified in at least 6 probands with classic PKU (PMIDs: 1301942, 8825928). It has been detected in the homozygous form (PMID: 1301942) as well as in trans with the pathogenic variant R408W (PMID: 8825928). This variant is absent from 1000G, ESP, and gnomAD databases. This variant results in a broken donor splice site, expected to result in the in-frame deletion of exon 2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PVS1_Moderate, PM2, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204457; hg19: chr12-103306568;