rs62507283

Positions:

• chr12-102852941-C-A
• chr12-102852941-C-G
• chr12-102852941-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3 PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.716G>T (p.Gly239Val) variant in PAH has been reported in 2 individuals with classic PKU (PMID 10394930, 31623983) detected with pathogenic variants p.R408W and IVS10–11g>a (PMID:32106880). This variant has extremely low frequency in gnomAD (MAF=0.00006). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229711/MONDO:0009861/006

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PAH ENST00000553106.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1 O:1
• Conservation: PhyloP100: 7.91

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 6 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.716G>T	p.Gly239Val	missense_variant	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.716G>T	p.Gly239Val	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.716G>T	p.Gly239Val	missense_variant	7/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000307000.7	c.701G>T	p.Gly234Val	missense_variant	8/14	5		ENSP00000303500
PAH	ENST00000549247.6	n.475G>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 32

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74264

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: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2023	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 23, 2020	The c.716G>T (p.Gly239Val) variant in PAH has been reported in 2 individuals with classic PKU (PMID 10394930, 31623983) detected with pathogenic variants p.R408W and IVS10–11g>a (PMID: 32106880). This variant has extremely low frequency in gnomAD (MAF=0.00006). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2023	Variant summary: PAH c.716G>T (p.Gly239Val) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of 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 250956 control chromosomes (gnomAD). c.716G>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Zschocke_1999, Sarkissian_2011, Sterl_2013, Reblova_2013, Rajabi_2019, Hillert_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, several other missense changes affecting the same amino acid (G239A/D/S) are reported in affected individuals (HGMD), supporting the clinical importance of this residue. The following publications have been ascertained in the context of this evaluation (PMID: 10394930, 23430918, 22526846, 23357515, 31623983, 32668217). Three submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1), likely pathogenic (n=1; i.e. the expert panel), or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2023	ClinVar contains an entry for this variant (Variation ID: 102800). 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 expected to disrupt PAH protein function. This variant disrupts the p.Gly239 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 7833954, 29499199; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with PAH-related conditions (PMID: 23357515; Invitae). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 239 of the PAH protein (p.Gly239Val). This variant is not present in population databases (gnomAD no frequency). -

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.8	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.96		Gain of catalytic residue at Q235 (P = 0.0634);.;
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

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: rs62507283; hg19: chr12-103246719;