12-102843665-C-G

Position:

• chr12-102843665-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_Moderate PM2 PP3 PM3

This summary comes from the ClinGen Evidence Repository: The c.1180G>C (p.Asp394His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID:8889590, 21147011, 31355225 ). This variant is absent in population databases. This variant was detected with pathogenic variants IVS10-11G>A (PMID:8889590); IVS11nt1g>c (IVS11+1G>C, PMID:10947211). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229371/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 5.01

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 7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1180G>C	p.Asp394His	missense_variant	11/13	ENST00000553106.6
PAH	NM_001354304.2	c.1180G>C	p.Asp394His	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1180G>C	p.Asp394His	missense_variant	11/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461620 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	Variant summary: PAH c.1180G>C (p.Asp394His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes (gnomAD). c.1180G>C has been reported in the literature in a homozygous and multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with phenotypes ranging from mild hyperphenylalaninemia to classic-phenylketonuria (e.g. Guldberg_1996, Dobrowolski_2011, Su_2019, Bik-Multanowski_2022, Hillert_2020); all reported compound heterozygous individuals carried a pathogenic second variant. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8889590, 21147011, 31355225, 35176108, 32668217). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters 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	Invitae	Jan 10, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 394 of the PAH protein (p.Asp394His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8889590, 31355225, 32668217). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102545). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. This variant disrupts the p.Asp394 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8268925, 8830172, 9634518, 32668217). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 17, 2020	The c.1180G>C (p.Asp394His) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8889590, 21147011, 31355225 ). This variant is absent in population databases. This variant was detected with pathogenic variants IVS10-11G>A (PMID: 8889590); IVS11nt1g>c (IVS11+1G>C, PMID: 10947211). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3. -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PAH: PM3:Very Strong, PM2, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.83	P;.
Vest4		0.71
MutPred		0.92		Gain of MoRF binding (P = 0.0674);.;
MVP		0.98
MPC		0.062
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs62516142; hg19: chr12-103237443;