NM_006623.4(PHGDH):c.1129G>A (p.Gly377Ser) AND PHGDH deficiency

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 16, 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:: RCV000004075.11

Allele description [Variation Report for NM_006623.4(PHGDH):c.1129G>A (p.Gly377Ser)]

NM_006623.4(PHGDH):c.1129G>A (p.Gly377Ser)

Gene:

PHGDH:phosphoglycerate dehydrogenase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p12

Genomic location:

Preferred name:

NM_006623.4(PHGDH):c.1129G>A (p.Gly377Ser)

HGVS:

NC_000001.11:g.119741817G>A
NG_009188.1:g.35022G>A
NM_006623.4:c.1129G>AMANE SELECT
NP_006614.2:p.Gly377Ser
NC_000001.10:g.120284440G>A
NM_006623.3:c.1129G>A
O43175:p.Gly377Ser

Protein change:

G377S; GLY377SER

Links:

UniProtKB: O43175#VAR_059029; OMIM: 606879.0005; dbSNP: rs267606948

NCBI 1000 Genomes Browser:

rs267606948

Molecular consequence:

NM_006623.4:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PHGDH deficiency
Synonyms:: Phosphoglycerate dehydrogenase deficiency
Identifiers:: MONDO: MONDO:0011152; MedGen: C1866174; OMIM: 601815

Recent activity

Clear Turn Off Turn On

right-handed parallel beta-helix repeat-containing protein [Blautia pseudococcoi...
right-handed parallel beta-helix repeat-containing protein [Blautia pseudococcoides]
gi|1957932539|gnl|PRJNA680355|I5Q86 5|gb|QQQ92440.1|

Protein
PREDICTED: uncharacterized protein LOC107349325 [Acropora digitifera]
PREDICTED: uncharacterized protein LOC107349325 [Acropora digitifera]
gi|1005468063|ref|XP_015770945.1|

Protein
uncharacterized protein LOC5504114 [Nematostella vectensis]
uncharacterized protein LOC5504114 [Nematostella vectensis]
gi|156359994|ref|XP_001625047.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024241	OMIM	no assertion criteria provided	Pathogenic (May 1, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 19235232, 28135894
SCV001584602	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21113737, 28135894, 19235232, 28492532
SCV004029011	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 19, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004049118	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Citations

PubMed

Infantile Serine Biosynthesis Defect Due to Phosphoglycerate Dehydrogenase Deficiency: Variability in Phenotype and Treatment Response, Novel Mutations, and Diagnostic Challenges.

Benke PJ, Hidalgo RJ, Braffman BH, Jans J, Gassen KLIV, Sunbul R, El-Hattab AW.

J Child Neurol. 2017 May;32(6):543-549. doi: 10.1177/0883073817690094. Epub 2017 Jan 31.

PubMed [citation]

PMID:: 28135894

Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics.

Tabatabaie L, de Koning TJ, Geboers AJ, van den Berg IE, Berger R, Klomp LW.

Hum Mutat. 2009 May;30(5):749-56. doi: 10.1002/humu.20934.

PubMed [citation]

PMID:: 19235232

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000024241.3

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

Description

In a Dutch brother and sister with phosphoglycerate dehydrogenase deficiency (PHGDHD; 601815), born of consanguineous parents, Tabatabaie et al. (2009) identified homozygosity for a 1129G-A transition in exon 10 of the PHGDH gene, resulting in a gly377-to-ser (G377S) substitution. Analysis of enzyme kinetics in patient-derived fibroblasts showed a markedly decreased V(max); transfection studies in HEK293 cells with overexpression of the G377S mutant resulted in a moderate decrease of V(max) without affecting K(m).

In 3 sisters (family 3) with PHGDHD, Benke et al. (2017) identified homozygosity for the c.1129G-A transition (c.1129G-A, NM_006623.3) in the PHGDH gene, resulting in a gly377-to-ser (G377S) substitution. In 2 sisters in an unrelated family (family 1) with PHGDHD, Benke et al. (2017) identified compound heterozygous mutations in the PHGDH gene: G377S and a 1-bp duplication (c.138+2dupT; 606879.0012). Serine and glycine were low in plasma and CSF in the patients from both families.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001584602.4

#	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 replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 377 of the PHGDH protein (p.Gly377Ser). This variant is present in population databases (rs267606948, gnomAD 0.003%). This missense change has been observed in individual(s) with phosphoglycerate dehydrogenase deficiency (PMID: 21113737, 28135894). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3871). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PHGDH protein function. Experimental studies have shown that this missense change affects PHGDH function (PMID: 19235232). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004029011.1

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

Description

Variant summary: PHGDH c.1129G>A (p.Gly377Ser) results in a non-conservative amino acid change located in the D-3-phosphoglycerate dehydrogenase, ASB domain (IPR045626) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251476 control chromosomes (gnomAD). c.1129G>A has been reported in the literature in individuals affected with Phosphoglycerate Dehydrogenase Deficiency (example: Tabatabaie_2009). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Tabatabaie_2009). The following publication has been ascertained in the context of this evaluation (PMID: 21113737). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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 Genome-Nilou Lab, SCV004049118.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine