12-102855193-A-G

Position:

• chr12-102855193-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):​c.649T>C​(p.Cys217Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C217F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1 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]

PAH (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 13) in uniprot entity PH4H_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102855192-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 12-102855193-A-G is Pathogenic according to our data. Variant chr12-102855193-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 102770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.649T>C	p.Cys217Arg	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.649T>C	p.Cys217Arg	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2	c.649T>C	p.Cys217Arg	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.649T>C	p.Cys217Arg	missense_variant	6/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.745T>C		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.634T>C	p.Cys212Arg	missense_variant	7/14	5		ENSP00000303500.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461844 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phenylketonuria Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys217 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8807319, 32668217). 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: 102770). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 18798839, 29499199, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 217 of the PAH protein (p.Cys217Arg). -
Uncertain significance, flagged submission	clinical testing	Counsyl	Dec 27, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 24, 2023	- -

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	0.79
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-12	D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.028	D;T
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.94		Gain of disorder (P = 0.0527);.;
MVP		1.0
MPC		0.29
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		1.0

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: rs62508718; hg19: chr12-103248971;