rs199475626

Positions:

• chr12-102866612-C-G
• chr12-102866612-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP4 PP3 PM2

This summary comes from the ClinGen Evidence Repository: The c.493G>C (p.Ala165Pro) variant in PAH has been reported in a French patient with mild PKU with p.Glu390Gly, but parents were not tested (PP4; PMID:26666653) This variant is absent from 1000G and ESP, and has extremely low frequency in ExAC/gnomAD: MAF 0.00001 (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.956 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229581/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2 O:1
• Conservation: PhyloP100: 5.24

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: 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.493G>C	p.Ala165Pro	missense_variant	5/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.493G>C	p.Ala165Pro	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2	c.493G>C	p.Ala165Pro	missense_variant	5/7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1385C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.493G>C	p.Ala165Pro	missense_variant	5/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.589G>C		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.478G>C	p.Ala160Pro	missense_variant	6/14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10850G>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251346 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461362 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727010

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2018	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 07, 2019	The c.493G>C (p.Ala165Pro) variant in PAH has been reported in a French patient with mild PKU with p.Glu390Gly, but parents were not tested (PP4; PMID: 26666653) This variant is absent from 1000G and ESP, and has extremely low frequency in ExAC/gnomAD: MAF 0.00001 (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.956 (PP3). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala165 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26666653; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 102701). This missense change has been observed in individual(s) with phenylkeonuria (PMID: 26666653). This variant is present in population databases (rs199475626, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 165 of the PAH protein (p.Ala165Pro). -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102700,VCV000805818, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.99		Loss of stability (P = 0.0358);.;
MVP		1.0
MPC		0.26
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199475626; hg19: chr12-103260390;