rs281865440

Variant names:

• chr12-102866600-G-A
• rs281865440
• NM_000277.3:c.505C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102866600-G-A
• chr12-102866600-G-C
• chr12-102866600-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3_Strong PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.505C>T (p.Arg169Cys) PAH variant has been identified in at least 3 compound heterozygous probands with mild HPA to classic PKU, with at least 1 proband excluding BH4 deficiency (PMIDs: 28771436, 30050108, 30747360). It has been detected in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). This variant occurs and a very low frequency of 0.00001194 in gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA267693/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 1.07
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902999 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.505C>T	p.Arg169Cys	missense_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.505C>T	p.Arg169Cys	missense_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2	c.505C>T	p.Arg169Cys	missense_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1373G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.505C>T	p.Arg169Cys	missense_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.601C>T		non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7	c.490C>T	p.Arg164Cys	missense_variant	Exon 6 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10862C>T		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251346 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460418 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726652

African (AFR) AF: 0.000150 AC: 5 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110754

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6

Nov 08, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000277.1(PAH):c.505C>T(R169C) is a missense variant classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the R169C mutation can be associated with any form of this disease. R169C has been observed in cases with relevant disease (PMID: 32668217, 30050108, 28982351, 28771436). Functional assessments of this variant are not available in the literature. R169C has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_000277.1(PAH):c.505C>T(R169C) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

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Inserm U 954, Faculté de Médecine de Nancy

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 18, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2019

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.505C>T (p.Arg169Cys) PAH variant has been identified in at least 3 compound heterozygous probands with mild HPA to classic PKU, with at least 1 proband excluding BH4 deficiency (PMIDs: 28771436, 30050108, 30747360). It has been detected in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). This variant occurs and a very low frequency of 0.00001194 in gnomAD. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate. -

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 169 of the PAH protein (p.Arg169Cys). This variant is present in population databases (rs281865440, gnomAD 0.003%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 28771436, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 125436). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. This variant disrupts the p.Arg169 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234516, 18299955, 21147011, 26666653, 28982351, 30459323). 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. -

not provided Pathogenic:1

Feb 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 26503515, 29499199, 32668217, 30050108, 28771436, 29316886, 21147011, 36845377) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Benign	0.0020
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.7	M;.
PhyloP100		1.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.62	P;.
Vest4		0.53
MVP		0.95
MPC		0.042
ClinPred		0.96	D
GERP RS		-0.060
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.57
gMVP		0.91
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281865440; hg19: chr12-103260378; COSMIC: COSV61018549;