rs199475697

chr12-102855228-TCATAGCAAGCATGGGTTTTATA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000277.3(PAH):c.592_613del(p.Tyr198SerfsTer136) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 10.0

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-102855228-TCATAGCAAGCATGGGTTTTATA-T is Pathogenic according to our data. Variant chr12-102855228-TCATAGCAAGCATGGGTTTTATA-T is described in ClinVar as [Pathogenic]. Clinvar id is 102746.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102855228-TCATAGCAAGCATGGGTTTTATA-T is described in Lovd as [Pathogenic]. Variant chr12-102855228-TCATAGCAAGCATGGGTTTTATA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PAH	NM_000277.3 linkuse as main transcript	c.592_613del	p.Tyr198SerfsTer136	frameshift_variant	6/13	ENST00000553106.6
PAH	NM_001354304.2 linkuse as main transcript	c.592_613del	p.Tyr198SerfsTer136	frameshift_variant	7/14
PAH	XM_017019370.2 linkuse as main transcript	c.592_613del	p.Tyr198SerfsTer66	frameshift_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.592_613del	p.Tyr198SerfsTer136	frameshift_variant	6/13	1	NM_000277.3	P1
PAH	ENST00000549111.5 linkuse as main transcript	n.688_709del		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.577_598del	p.Tyr193SerfsTer136	frameshift_variant	7/14	5
PAH	ENST00000551988.5 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251328

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00000274

AC:

AN:

1461738

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26481238). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000102746). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 23, 2023	ClinVar contains an entry for this variant (Variation ID: 102746). This premature translational stop signal has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 9359039, 21890392, 24301756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199475697, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Tyr198Serfs*136) 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Mar 16, 2023	The c.592_613del (p.Tyr198fs) variant in PAH is a frameshift variant predicted to cause termination at amino acid 334 in exon 10, resulting in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in multiple patients with PAH deficiency with pathogenic variants: c.782G>A (p.Arg261Gln) (PMID: 21890392); c.1222C>T (p.Arg408Trp) (PMID:26481238); c.969+1G>A (IVS9 + 1G>A) (PMID:18321666); c.311C>A (p.A104D), c.755G>A (p.R252Q) (PMID:23942198). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PM3_strong, PP4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 06, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 25, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 21, 2016	Variant summary: This c.592_613del22 variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 198 and leads to a premature termination codon 136 amino acids downstream. It is predicted to cause a truncated or absent PAH protein. Loss-of-function due to mutations in this gene is an established disease mechanism in Phenylketoneuria. This variant was not found in approximately 121322 chromosomes from the broad and large populations of ExAC. This variant has been recurrently reported as a causative mutation in patients with Phenylketoneuria. The region this variant is located is a mutational hot-spot where other similar pathogenic frameshift variants (such as c.586del22, c.589del22, c.590del23 and c.593del22) (source: HGMD) have been reported. Reputable databases have also classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PAH NM_000277.2 exon 6 p.Tyr198Serfs*136 (c.592_613del): This variant has been reported in the literature in the homozygous state in two individuals with phenylketonuria (Daniele 2009 PMID:19292873, Ajami 2013 PMID:24301756) and has been reported in the PAH Consortium Database (www.biopku.org). This variant is present in 0.01% (5/35428) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-103249006-TCATAGCAAGCATGGGTTTTATA-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:102746). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a deletion of 22 nucleotides and creates a premature stop codon 136 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene (Eisensmith 1992 PMID:1301187, Guldberg 1998 PMID:9634518). In summary, this variant is classified as pathogenic based on the data above. -

not provided

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21147011, 8069318, 19292873, 28676969, 24301756, 17096675, 26701937, 22572109, 10767174) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2021

The c.592_613del22 (p.Y198Sfs*136) alteration, located in exon 6 (coding exon 6) of the PAH gene, consists of a deletion of 22 nucleotides from position 592 to 613, causing a translational frameshift with a predicted alternate stop codon after 136 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in the homozygous state and in trans with a second alteration in patients with phenylalanine hydroxylase deficiency (Daniele, 2009; Kostandyan, 2011; Ajami, 2013; Carducci, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over