rs62506950

Positions:

• chr12-102894820-A-AG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM3 PP4_Moderate PVS1 PM2

This summary comes from the ClinGen Evidence Repository: Variant classified as Pathogenic using the following criteria: PVS1; PM2; PM3; PP4_Moderate. PVS1: frameshift variant in exon 2 of 13, predicted to result in PTC with removal of >10% of the protein and NMD; PM2: absent from ExAC, gnomAD, 1000G, ESP. PP4_Moderate; PM3: c.266_267insC seen on 2 PKU alleles, with BH4 deficiency ruled out (PMID:21147011). Detected with pathogenic variants IVS12+1G>A and p.I65T (PMID:9452062); and p.Pro281Leu (Likely Pathogenic per ClinGen PAH VCEP, PMID:26666653). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229503/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:2
• Conservation: PhyloP100: 2.99

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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.266_267insC	p.Ala90CysfsTer12	frameshift_variant	3/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.863-9876dup		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.266_267insC	p.Ala90CysfsTer12	frameshift_variant	4/14		NP_001341233.1
PAH	XM_017019370.2	c.266_267insC	p.Ala90CysfsTer12	frameshift_variant	3/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.266_267insC	p.Ala90CysfsTer12	frameshift_variant	3/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251452 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135894

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2022	Variant summary: PAH c.266dupC (p.Ala90CysfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251452 control chromosomes. c.266dupC is also refered to in the literature as P89fsinsC. It has been reported in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) who are compound heterozygotes for c.266dupC in combination with other PAH-disease related variants (example Michiels_1998, Perez_1999, Aulehla-Scholz_2003, Dobrowolski_2011, Jeannesson-Thivisol_2015, Kuznetcova_2019). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 10, 2023	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 08, 2020	Variant classified as Pathogenic using the following criteria: PVS1; PM2; PM3; PP4_Moderate. PVS1: frameshift variant in exon 2 of 13, predicted to result in PTC with removal of >10% of the protein and NMD; PM2: absent from ExAC, gnomAD, 1000G, ESP. PP4_Moderate; PM3: c.266_267insC seen on 2 PKU alleles, with BH4 deficiency ruled out (PMID: 21147011). Detected with pathogenic variants IVS12+1G>A and p.I65T (PMID: 9452062); and p.Pro281Leu (Likely Pathogenic per ClinGen PAH VCEP, PMID: 26666653). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 05, 2023	This sequence change creates a premature translational stop signal (p.Ala90Cysfs*12) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of PAH-related conditions (PMID: 9452062, 24368688, 26666653). This variant is also known as P89fsinsC. ClinVar contains an entry for this variant (Variation ID: 102642). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2017	- -

not provided Other:2

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
not provided, flagged submission	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

Computational scores

Source: dbNSFP v4.3

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: rs62506950; hg19: chr12-103288598;