NM_007198.4:c.260C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_007198.4(PLPBP):c.260C>T(p.Pro87Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000634 in 1,609,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

PLPBP
NM_007198.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.52

Publications

4 publications found

Variant links:

Genes affected

PLPBP (HGNC:9457): (pyridoxal phosphate binding protein) This gene encodes a pyridoxal 5'-phosphate binding protein involved in the homeostatic regulation of intracellular pyridoxal 5'-phosphate. This gene has a tumor suppressive effect on hepatocellular carcinoma and other solid tumors of epithelial origin. Naturally occurring mutations in this gene are associated with a pyridoxine-dependent epilepsy. [provided by RefSeq, Mar 2017]

PLPBP Gene-Disease associations (from GenCC):

epilepsy, early-onset, vitamin B6-dependent
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
pyridoxine-dependent epilepsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PLPBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-37766296-C-T is Pathogenic according to our data. Variant chr8-37766296-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLPBP	NM_007198.4 link	c.260C>T	p.Pro87Leu	missense_variant	Exon 4 of 8	ENST00000328195.8	NP_009129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLPBP	ENST00000328195.8 link	c.260C>T	p.Pro87Leu	missense_variant	Exon 4 of 8	1	NM_007198.4	ENSP00000333551.3		O94903

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000202

AC:

AN:

247412

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000666

AC:

AN:

1457048

Hom.:

Cov.:

AF XY:

0.0000662

AC XY:

AN XY:

724842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33086

American (AMR)

AF:

0.00

AC:

AN:

43858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39396

South Asian (SAS)

AF:

0.00

AC:

AN:

85488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000838

AC:

AN:

1109834

Other (OTH)

AF:

0.0000664

AC:

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 87 of the PROSC protein (p.Pro87Leu). This variant is present in population databases (rs755946598, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of pyridoxine-dependent epilepsy (PMID: 27912044, 28391250, 29689137, 33766999). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 374856). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PROSC protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PROSC function (PMID: 27912044, 29689137). For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29689137, 28914444, 28391250, 27912044, 33766999, 33728241, 36007526, 33425341) -

Epilepsy, early-onset, vitamin B6-dependent

Pathogenic:2

Jan 16, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as compound heterozygous change and as homozygous change in patients with Epilepsy, early-onset, vitamin B6-dependent (PMID: 27912044, 28391250). Based on complementation studies in PROSC-deficient E. coli the p.Pro87Leu protein appeared to retained some function (PMID: 27912044). Additional functional studies in bacteria showed that the p.Pro87Leu variant results in decreased protein solubility (PMID: 29689137). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (7/278808) and is absent in the homozygous state, thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.260C>T (p.Pro87Leu) variant is classified as Likely Pathogenic. -

Aug 14, 2023

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;.;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Benign

-0.84

PhyloP100

7.5

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.024

D;D;D;D

Sift4G

Uncertain

0.057

T;T;T;D

Polyphen

0.041

B;.;.;.

Vest4

0.84

MutPred

0.59

Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);.;.;

MVP

0.51

MPC

0.92

ClinPred

0.96

GERP RS

5.3

PromoterAI

0.0082

Neutral

(source)

Varity_R

0.64

gMVP

0.65

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_007198.4:c.260C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over