NM_000281.4(PCBD1):c.259G>T (p.Glu87Ter) AND Pterin-4 alpha-carbinolamine dehydratase 1 deficiency

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000018286.35

Allele description [Variation Report for NM_000281.4(PCBD1):c.259G>T (p.Glu87Ter)]

NM_000281.4(PCBD1):c.259G>T (p.Glu87Ter)

Gene:

PCBD1:pterin-4 alpha-carbinolamine dehydratase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_000281.4(PCBD1):c.259G>T (p.Glu87Ter)

Other names:

E86*

HGVS:

NC_000010.11:g.70884006C>A
NG_008646.1:g.9779G>T
NM_000281.4:c.259G>TMANE SELECT
NM_001289797.2:c.112G>T
NM_001323004.2:c.216+1146G>T
NP_000272.1:p.Glu87Ter
NP_001276726.1:p.Glu38Ter
NC_000010.10:g.72643763C>A
NM_000281.2:c.259G>T
NM_000281.3:c.259G>T

Note:

NCBI staff reviewed the sequence information reported in PubMed 9585615 Fig. 1C to determine the location of this allele on the current reference sequence.

Protein change:

E38*; GLU86TER

Links:

OMIM: 126090.0001; OMIM: 126090.0004; dbSNP: rs104894172

NCBI 1000 Genomes Browser:

rs104894172

Molecular consequence:

NM_001323004.2:c.216+1146G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000281.4:c.259G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001289797.2:c.112G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Pterin-4 alpha-carbinolamine dehydratase 1 deficiency
Synonyms:: CADH DEFICIENCY; Hyperphenylalaninemia, BH4-deficient, D; Hyperphenylalaninemia due to dehydratase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009908; MedGen: C1849700; Orphanet: 238583; OMIM: 264070

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038565	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 1998)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 8352282, 8618906, 9585615
SCV000915479	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25333069, 24204001, 8352282, 9585615, 8618906 Citation Link,
SCV002247361	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8352282, 9585615, 8618906, 24204001, 28492532
SCV002810399	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 4, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Disease variants in genomes of 44 centenarians.

Freudenberg-Hua Y, Freudenberg J, Vacic V, Abhyankar A, Emde AK, Ben-Avraham D, Barzilai N, Oschwald D, Christen E, Koppel J, Greenwald B, Darnell RB, Germer S, Atzmon G, Davies P.

Mol Genet Genomic Med. 2014 Sep;2(5):438-50. doi: 10.1002/mgg3.86. Epub 2014 Jun 15.

PubMed [citation]

PMID:: 25333069
PMCID:: PMC4190879

Mutation in the 4a-carbinolamine dehydratase gene leads to mild hyperphenylalaninemia with defective cofactor metabolism.

Citron BA, Kaufman S, Milstien S, Naylor EW, Greene CL, Davis MD.

Am J Hum Genet. 1993 Sep;53(3):768-74.

PubMed [citation]

PMID:: 8352282
PMCID:: PMC1682436

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000038565.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a 1-year-old Caucasian male with BH4-deficient hyperphenylalaninemia-D (HPABH4D; 264070), Citron et al. (1993) found compound heterozygosity for 2 mutations in the PCBD1 gene: a c.259G-T transversion, resulting in a glu87-to-ter (E87X) substitution, and a c.244T-C transition, resulting in a cys82-to-arg (C82R; 126090.0002) substitution. The nonsense mutation came from the father and the missense mutation from the mother. The patient was found to have mildly increased phenylalanine at newborn screening.

Johnen et al. (1995) characterized the wildtype form of pterin-4-alpha-carbinolamine dehydratase and the 2 naturally occurring mutants C82R and Q87X. Considering the decrease in specific activity and stability of the mutants, they concluded that the patient probably had less than 10% residual dehydratase activity, which could be responsible for the mild hyperphenylalaninemia and the high 7-biopterin levels.

In 2 sibs of Ashkenazi Jewish descent with hyperphenylalaninemia associated with high levels of 7-biopterin (BIODEF273; BIODEF344), Thony et al. (1998) identified a homozygous c.279G-T transversion in the PCBD1 gene, resulting in a glu86-to-ter (E86X) substitution. The first methionine was not included in the numbering used by Thony et al. (1998). Both sibs developed normally without pharmacologic or dietary treatment.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000915479.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The PCBD1 c.259G>T (p.Glu87Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. This variant has been reported in at least two studies in which it is found in a total of three individuals with BH4-deficient hyperphenylalaninemia, including two siblings of Ashkenazi Jewish descent who were homozygous for the variant and another individual who was compound heterozygous for the variant and a missense variant (Citron et al. 1993; ThÃ¶ny et al. 1998). The p.Glu87Ter variant was found in a heterozygous state in both unaffected parents of the homozygous siblings and in the unaffected father of the compound heterozygote. The variant was also found in a heterozygous state in a centenarian from a longevity study (Freudenberg-Hua et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the p.Glu87Ter variant in cell lines revealed little to no residual dehydratase activity, with most of the protein found in the insoluble fraction and no detectable PCBD1 protein. The residual mutant protein was still able to bind substrate with a Km that did not significantly differ from wild type (Johnen et al. 1995; ThÃ¶ny et al. 1998; FerrÃ¨ et al. 2014). Based on the evidence and the potential impact of stop-gained variants, the p.Glu87Ter variant is classified as likely pathogenic for BH4-deficient hyperphenylalaninemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002247361.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Glu87*) in the PCBD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the PCBD1 protein. This variant is present in population databases (rs104894172, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with clinical features of biopterin deficient hyperphenylalanemia (PMID: 8352282, 9585615). This variant is also known as E86X . ClinVar contains an entry for this variant (Variation ID: 16795). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PCBD1 function (PMID: 8618906). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PCBD1 protein in which other variant(s) (p.Gln98*) have been determined to be pathogenic (PMID: 24204001). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002810399.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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