rs62507337

Positions:

• chr12-102852939-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_Supporting PM5_Supporting PP3_Strong

This summary comes from the ClinGen Evidence Repository: The c.718T>G (p.Phe240Val) variant in PAH has not been reported in the literature detected in an affected patient to our knowledge. This variant has a Pop Max allele frequency of [0.00001271] for [ENF] chromosomes by gnomAD v4.1.0, which is lower than the ClinGen PAH threshold (≤ 0.0002) and therefore meets PM2_Supporting. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.978. A different likely pathogenic missense change (p.Phe240Ser) has been seen before. In summary, this variant meets criteria to be classified as Likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP3_strong, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229713/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PAH ENST00000553106.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:5 O:1
• Conservation: PhyloP100: 9.32

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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.718T>G	p.Phe240Val	missense_variant	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.718T>G	p.Phe240Val	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.718T>G	p.Phe240Val	missense_variant	7/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000307000.7	c.703T>G	p.Phe235Val	missense_variant	8/14	5		ENSP00000303500
PAH	ENST00000549247.6	n.477T>G		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727222

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 240 of the PAH protein (p.Phe240Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe240 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 102801). -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Nov 09, 2020	The c.718T>G (p.Phe240Val) variant in PAH has not been reported in the literature detected in an affected patient to our knowledge. This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.978. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3. -

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 29, 2024

Variant summary: PAH c.718T>G (p.Phe240Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.718T>G in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 102801). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2022

The c.718T>G (p.F240V) alteration is located in exon 7 (coding exon 7) of the PAH gene. This alteration results from a T to G substitution at nucleotide position 718, causing the phenylalanine (F) at amino acid position 240 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
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	0.95	D
MutationAssessor	Pathogenic	4.4	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.97		Loss of methylation at R243 (P = 0.1541);.;
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
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: rs62507337; hg19: chr12-103246717;