NM_000281.4(PCBD1):c.292C>T (p.Gln98Ter) AND Pterin-4 alpha-carbinolamine dehydratase 1 deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 18, 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:: RCV000018290.38

Allele description [Variation Report for NM_000281.4(PCBD1):c.292C>T (p.Gln98Ter)]

NM_000281.4(PCBD1):c.292C>T (p.Gln98Ter)

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.292C>T (p.Gln98Ter)

HGVS:

NC_000010.11:g.70883973G>A
NG_008646.1:g.9812C>T
NM_000281.4:c.292C>TMANE SELECT
NM_001289797.2:c.145C>T
NM_001323004.2:c.216+1179C>T
NP_000272.1:p.Gln98Ter
NP_001276726.1:p.Gln49Ter
NC_000010.10:g.72643730G>A
NM_000281.2:c.292C>T
NM_000281.3:c.292C>T

Protein change:

Q49*; GLN98TER

Links:

OMIM: 126090.0005; dbSNP: rs121913015

NCBI 1000 Genomes Browser:

rs121913015

Molecular consequence:

NM_001323004.2:c.216+1179C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000281.4:c.292C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001289797.2:c.145C>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
SCV000038569	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9585615, 24848070
SCV001752476	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 10, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002252383	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24204001, 28492532
SCV003813183	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848890	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jan 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9585615, 24204001, 24848070, 25741868

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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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Hyperphenylalaninemia with high levels of 7-biopterin is associated with mutations in the PCBD gene encoding the bifunctional protein pterin-4a-carbinolamine dehydratase and transcriptional coactivator (DCoH).

Thöny B, Neuheiser F, Kierat L, Blaskovics M, Arn PH, Ferreira P, Rebrin I, Ayling J, Blau N.

Am J Hum Genet. 1998 Jun;62(6):1302-11.

PubMed [citation]

PMID:: 9585615
PMCID:: PMC1377166

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000038569.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 unrelated patients (BIODEF272 and BIODEF264) with hyperphenylalaninemia associated with high levels of 7-biopterin (HPABH4D; 264070), Thony et al. (1998) identified a homozygous c.312C-T transition in the PCBD1 gene, resulting in a gln97-to-ter (Q97X) substitution. Growth and development were normal in both patients. The first methionine was not included in the numbering used by Thony et al. (1998).

Simaite et al. (2014) referred to this mutation as a c.292C-T transition, resulting in a gln98-to-ter (Q98X) substitution.

#	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 Fulgent Genetics, Fulgent Genetics, SCV001752476.2

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002252383.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Gln98*) in the PCBD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the PCBD1 protein. This variant is present in population databases (rs121913015, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with clinical features of tetrahydrobiopterin-deficient hyperphenylalaninemia (PMID: 24204001). This variant is also known as Q97X. ClinVar contains an entry for this variant (Variation ID: 16799). 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: 24204001). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

#	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 Revvity Omics, Revvity, SCV003813183.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848890.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Gln98X variant in PCBD1 (also reported in literature as p.Gln97X) has been reported in 3 homozygous individuals and 2 compound heterozygous individuals with hyperphenylalaninemia, two of which were also reported to have early onset diabetes (Thony 1998 PMID: 9585615, Ferré 2014 PMID: 24204001, Simaite 2014 PMID: 24848070). It has also been identified in 0.023% (30/129080) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 16799). This nonsense variant leads to a premature termination codon at position 98. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, in vitro functional studies suggest that this variant impacts protein expression or function (Thony 1998 PMID: 9585615, Ferré 2014 PMID: 24204001). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive tetrahydrobiopterin deficiency. ACMG/AMP Criteria applied: PVS1_Moderate, PM3, PS3_Supporting, PM2_Supporting.

#	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

Last Updated: Sep 29, 2024

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