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NM_000190.4(HMBS):c.799G>A (p.Val267Met) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Dec 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:
RCV000430573.4

Allele description [Variation Report for NM_000190.4(HMBS):c.799G>A (p.Val267Met)]

NM_000190.4(HMBS):c.799G>A (p.Val267Met)

Gene:
HMBS:hydroxymethylbilane synthase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q23.3
Genomic location:
Preferred name:
NM_000190.4(HMBS):c.799G>A (p.Val267Met)
HGVS:
  • NC_000011.10:g.119092785G>A
  • NG_008093.1:g.12909G>A
  • NM_000190.4:c.799G>AMANE SELECT
  • NM_001024382.2:c.748G>A
  • NM_001258208.2:c.679G>A
  • NM_001258209.2:c.628G>A
  • NP_000181.2:p.Val267Met
  • NP_001019553.1:p.Val250Met
  • NP_001245137.1:p.Val227Met
  • NP_001245138.1:p.Val210Met
  • LRG_1076t1:c.799G>A
  • LRG_1076t2:c.748G>A
  • LRG_1076:g.12909G>A
  • LRG_1076p1:p.Val267Met
  • LRG_1076p2:p.Val250Met
  • NC_000011.9:g.118963495G>A
  • NM_000190.3:c.799G>A
Protein change:
V210M
Links:
dbSNP: rs1057521126
NCBI 1000 Genomes Browser:
rs1057521126
Molecular consequence:
  • NM_000190.4:c.799G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001024382.2:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258208.2:c.679G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258209.2:c.628G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000521150GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Likely pathogenic
(May 28, 2020) 		germlineclinical testing

Citation Link,

SCV004294973Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 11, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Molecular epidemiology and diagnosis of PBG deaminase gene defects in acute intermittent porphyria.

Puy H, Deybach JC, Lamoril J, Robreau AM, Da Silva V, Gouya L, Grandchamp B, Nordmann Y.

Am J Hum Genet. 1997 Jun;60(6):1373-83.

PubMed [citation]
PMID:
9199558
PMCID:
PMC1716106

Molecular analysis of porphobilinogen (PBG) deaminase gene mutations in acute intermittent porphyria: first study in patients of Slavic origin.

Rosipal R, Puy H, Lamoril J, Martasek P, Nordmann Y, Deybach JC.

Scand J Clin Lab Invest. 1997 May;57(3):217-24.

PubMed [citation]
PMID:
9238757
See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000521150.4

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

Description

Published functional studies demonstrate a damaging effect with severely impaired mutant enzyme activity (Lenglet et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9199558, 9238757, 17298216, 17298218, 27769855, 29360981)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294973.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 267 of the HMBS protein (p.Val267Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute intermittent porphyria (PMID: 9199558, 9238757; Invitae). ClinVar contains an entry for this variant (Variation ID: 381651). 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 expected to disrupt HMBS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMBS function (PMID: 29360981). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024