rs1555204295

Positions:

• chr12-102851689-G-A
• chr12-102851689-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_Supporting PVS1 PP4

This summary comes from the ClinGen Evidence Repository: The c.910C>T (p.Gln304Ter) variant in PAH has been reported in at least 1 individual with PKU however without indication of the genotype (BH4 deficiency not ruled out) (PMID:23357515) . This variant occurs in exon 8 of 13 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to result in a truncated protein (with truncation of >10% of the encoded protein) or mRNA subject to nonsense-mediated decay. The c.910C>T variant is absent from gnomAD and the ESP population databases. Based on available information, this variant is considered to be pathogenic. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020892/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH ENST00000553106.6 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.60

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 Pathogenic. Variant got 10 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.
• 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.910C>T	p.Gln304Ter	stop_gained, splice_region_variant	8/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.910C>T	p.Gln304Ter	stop_gained, splice_region_variant	9/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.910C>T	p.Gln304Ter	stop_gained, splice_region_variant	8/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 15, 2023	The c.910C>T (p.Gln304Ter) variant in PAH has been reported in at least 1 individual with PKU however without indication of the genotype (BH4 deficiency not ruled out) (PMID: 23357515) . This variant occurs in exon 8 of 13 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to result in a truncated protein (with truncation of >10% of the encoded protein) or mRNA subject to nonsense-mediated decay. The c.910C>T variant is absent from gnomAD and the ESP population databases. Based on available information, this variant is considered to be pathogenic. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2020	Variant summary: PAH c.910C>T (p.Gln304X) 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 was absent in 250994 control chromosomes. c.910C>T has been reported in the literature in at-least one individual affected with Phenylalanine Hydroxylase Deficiency, in locus specific database and subsequently cited by others (example, Reblova_2013, Wettstein_2015, Yan_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		5.5
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	Pathogenic	0.77
SpliceAI score (max)		0.13		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: rs1555204295; hg19: chr12-103245467;