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NM_006623.4(PHGDH):c.2T>C (p.Met1Thr) AND PHGDH deficiency

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Apr 11, 2023
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:
RCV001806759.7

Allele description [Variation Report for NM_006623.4(PHGDH):c.2T>C (p.Met1Thr)]

NM_006623.4(PHGDH):c.2T>C (p.Met1Thr)

Gene:
PHGDH:phosphoglycerate dehydrogenase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p12
Genomic location:
Preferred name:
NM_006623.4(PHGDH):c.2T>C (p.Met1Thr)
HGVS:
  • NC_000001.11:g.119712024T>C
  • NG_009188.1:g.5229T>C
  • NM_006623.4:c.2T>CMANE SELECT
  • NP_006614.2:p.Met1Thr
  • NC_000001.10:g.120254647T>C
  • NM_006623.3:c.2T>C
Protein change:
M1T
Links:
dbSNP: rs951372478
NCBI 1000 Genomes Browser:
rs951372478
Molecular consequence:
  • NM_006623.4:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_006623.4:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002051138Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Dec 15, 2021)
germlineclinical testing

Citation Link,

SCV002152516Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 1, 2022)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004049030Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Apr 11, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis.

Bourque DK, Cloutier M, Kernohan KD, Bareke E, Grynspan D, Michaud J; Care4Rare Canada Consortium., Boycott KM.

Am J Med Genet A. 2019 May;179(5):813-816. doi: 10.1002/ajmg.a.61076. Epub 2019 Mar 5.

PubMed [citation]
PMID:
30838783

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
See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002051138.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: PHGDH c.2T>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next alternative downstream in-frame start codon (Met 96) is located at the end of exon 2. Therefore, a severe outcome is predicted. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251114 control chromosomes. To our knowledge, no occurrence of c.2T>C in individuals affected with Phosphoglycerate Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. However, the HGMD database lists at-least one other variant resulting in the same translational impact, namely c.1A>C (p.M1?) that has been associated with a phenotype of Neu-Laxova syndrome, an allelic autosomal recessive disorder with a more severe phenotype that usually results in neonatal death. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002152516.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1331415). Disruption of the initiator codon has been observed in individual(s) with Neu-Laxova syndrome (PMID: 30838783). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PHGDH mRNA. The next in-frame methionine is located at codon 96.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV004049030.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 28, 2024