NM_007198.4(PLPBP):c.370_373del (p.Asp124fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 30, 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:: RCV000599011.4

Allele description [Variation Report for NM_007198.4(PLPBP):c.370_373del (p.Asp124fs)]

NM_007198.4(PLPBP):c.370_373del (p.Asp124fs)

Gene:

PLPBP:pyridoxal phosphate binding protein [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

8p11.23

Genomic location:

Preferred name:

NM_007198.4(PLPBP):c.370_373del (p.Asp124fs)

HGVS:

NC_000008.11:g.37772805_37772808del
NG_053030.1:g.16053_16056del
NM_001349346.2:c.370_373del
NM_001349347.2:c.364_367del
NM_001349348.2:c.214_217del
NM_007198.4:c.370_373delMANE SELECT
NP_001336275.1:p.Asp124fs
NP_001336276.1:p.Asp122fs
NP_001336277.1:p.Asp72fs
NP_009129.1:p.Asp124fs
NC_000008.10:g.37630321_37630324del
NC_000008.10:g.37630323_37630326del
NM_007198.3:c.370_373del
NM_007198.3:c.370_373delGACA

Protein change:

D122fs

Links:

dbSNP: rs755595256

NCBI 1000 Genomes Browser:

rs755595256

Molecular consequence:

NM_001349346.2:c.370_373del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001349347.2:c.364_367del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001349348.2:c.214_217del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_007198.4:c.370_373del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000710194	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Dec 4, 2017)	germline	clinical testing	Citation Link,
SCV003459806	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27912044, 30160830, 33977028, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000710194

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Dec 4, 2017)

germline

clinical testing

Citation Link,

SCV003459806

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B(6)-Dependent Epilepsy.

Darin N, Reid E, Prunetti L, Samuelsson L, Husain RA, Wilson M, El Yacoubi B, Footitt E, Chong WK, Wilson LC, Prunty H, Pope S, Heales S, Lascelles K, Champion M, Wassmer E, Veggiotti P, de Crécy-Lagard V, Mills PB, Clayton PT.

Am J Hum Genet. 2016 Dec 1;99(6):1325-1337. doi: 10.1016/j.ajhg.2016.10.011.

PubMed [citation]

PMID:: 27912044
PMCID:: PMC5142116

Diagnostic clarity of exome sequencing following negative comprehensive panel testing in the neonatal intensive care unit.

Kernohan KD, Hartley T, Naumenko S, Armour CM, Graham GE, Nikkel SM, Lines M, Geraghty MT, Richer J, Mears W, Boycott KM, Dyment DA.

Am J Med Genet A. 2018 Jul;176(7):1688-1691. doi: 10.1002/ajmg.a.38838. No abstract available.

PubMed [citation]

PMID:: 30160830

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000710194.2

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

Description

The c.370_373delGACA variant in the PROSC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.370_373delGACA variant causes a frameshift starting with codon Aspartic acid 124, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Asp124LysfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.370_373delGACA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.370_373delGACA as a pathogenic variant.

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

From Invitae, SCV003459806.2

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

Description

This sequence change creates a premature translational stop signal (p.Asp124Lysfs*2) in the PROSC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROSC are known to be pathogenic (PMID: 27912044). This variant is present in population databases (rs755595256, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive pyridoxine-dependent epilepsy (PMID: 30160830, 33977028). ClinVar contains an entry for this variant (Variation ID: 503895). 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

Last Updated: Feb 28, 2024

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