rs121907987

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_006623.4(PHGDH):c.1468G>A(p.Val490Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

PHGDH
NM_006623.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

PHGDH (HGNC:8923): (phosphoglycerate dehydrogenase) This gene encodes the enzyme which is involved in the early steps of L-serine synthesis in animal cells. L-serine is required for D-serine and other amino acid synthesis. The enzyme requires NAD/NADH as a cofactor and forms homotetramers for activity. Mutations in this gene have been found in a family with congenital microcephaly, psychomotor retardation and other symptoms. Multiple alternatively spliced transcript variants have been found, however the full-length nature of most are not known. [provided by RefSeq, Aug 2011]

PHGDH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-119743906-G-A is Pathogenic according to our data. Variant chr1-119743906-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3867.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
PHGDH	NM_006623.4 linkuse as main transcript	c.1468G>A	p.Val490Met	missense_variant	12/12	ENST00000641023.2	NP_006614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHGDH	ENST00000641023.2 linkuse as main transcript	c.1468G>A	p.Val490Met	missense_variant	12/12		NM_006623.4	ENSP00000493175	P1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

249930

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.0000713

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461510

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PHGDH deficiency

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS3+PM3+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 490 of the PHGDH protein (p.Val490Met). This variant is present in population databases (rs121907987, gnomAD 0.2%). This missense change has been observed in individuals with phosphoglycerate dehydrogenase deficiency (PMID: 11055895, 11751922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3867). 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 not expected to disrupt PHGDH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PHGDH function (PMID: 11055895, 11751922). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 23, 2017	Variant summary: The PHGDH c.1468G>A (p.Val490Met) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 13/123042 control chromosomes at a frequency of 0.0001059, which does not exceed the estimated maximal expected allele frequency of a pathogenic PHGDH variant (0.0026352). The variant has been reported in the homozygous state in numerousffected individuals, and functional studies showed the variant to result in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp_2000, Pind_2002). In addition, one reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jun 05, 2020	This variant has been reported in several individuals affected with phosphoglycerate dehydrogenase deficiency and was found to segregate with the disease in related individuals (PMID: 11055895, 11751922). Functional studies have shown that this change disrupts PHGDH enzymatic activity in vitro (PMID: 11055895, 11751922). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00014 (40/281324) and thus is presumed to be rare. In silico analyses are suggestive of deleterious effect of the c.1468G>A (p.Val490Met) variant on protein function. Based on the available evidence, the c.1468G>A (p.Val490Met) variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Neu-Laxova syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.1468G>A(p.Val490Met) in PHGDH gene has been reported previously in homozygous state in multiple indidviduals with 3-phosphoglycerate dehydrogenase (PHGDH) deficiency (Klomp LW, et al., 2000, Pind S, et al., 2002). Experimental studies show that the variant results in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp LW, et al., 2000, Pind S, et al., 2002). The c.1468G>A variant has 0.01% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Valine at position 490 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict no damaging effect on protein structure and function for this variant. The amino acid change p.Val490Met in PHGDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

PHGDH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The PHGDH c.1468G>A variant is predicted to result in the amino acid substitution p.Val490Met. This variant has been reported in individuals with autosomal recessive 3-phosphoglycerate dehydrogenase deficiency (Klomp et al. 2000. PubMed ID: 11055895; Ni et al. 2019. PubMed ID: 31903955; Lindstrand et al. 2022. PubMed ID: 36066546). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 02, 2019

ACMG classification criteria: PS3, PS4, PP1, PP3 -

PHGDH deficiency;C4551478:Neu-Laxova syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.10

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.46

MutationTaster

Benign

0.068

A;A

ClinPred

0.091

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over