12-102894776-G-A

Variant names:

• chr12-102894776-G-A
• rs62642929
• NM_000277.3:c.311C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.311C>T (p.Ala104Val) missense variant in PAH has been reported in 1 Chinese patient with classic PKU (Phe >1200umol/L; BH4 deficiency excluded) (PMID:29499199; PP4_Moderate). This variant is absent from population databases (PM2), and is located at same location a c.311C>A (p.Ala104Asp), reported as Pathogenic in ClinVar (VarID:102650). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386304006/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 2.77
• Publications: 1 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 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.
• 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.311C>T	p.Ala104Val	missense_variant	Exon 3 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.311C>T	p.Ala104Val	missense_variant	Exon 4 of 14		NP_001341233.1
PAH	XM_017019370.2	c.311C>T	p.Ala104Val	missense_variant	Exon 3 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.863-9922G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.311C>T	p.Ala104Val	missense_variant	Exon 3 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Jul 30, 2022

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.311C>T (p.Ala104Val) missense variant in PAH has been reported in 1 Chinese patient with classic PKU (Phe >1200umol/L; BH4 deficiency excluded) (PMID: 29499199; PP4_Moderate). This variant is absent from population databases (PM2), and is located at same location a c.311C>A (p.Ala104Asp), reported as Pathogenic in ClinVar (VarID:102650). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.72	N;.;.;.
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.38	N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.54	T;T;T;T
Sift4G	Benign	0.50	T;T;T;.
Polyphen		0.0030	B;.;.;.
Vest4		0.42
MutPred		0.28		Loss of loop (P = 0.0512);.;Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.94
MPC		0.031
ClinPred		0.66	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.88
Mutation Taster		=16/84	disease causing

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: rs62642929; hg19: chr12-103288554;