NM_000190.4(HMBS):c.925C>T (p.Pro309Ser) AND Acute intermittent porphyria

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 8, 2017
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:: RCV001108009.5

Allele description [Variation Report for NM_000190.4(HMBS):c.925C>T (p.Pro309Ser)]

NM_000190.4(HMBS):c.925C>T (p.Pro309Ser)

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.925C>T (p.Pro309Ser)

HGVS:

NC_000011.10:g.119093122C>T
NG_008093.1:g.13246C>T
NM_000190.4:c.925C>TMANE SELECT
NM_001024382.2:c.874C>T
NM_001258208.2:c.805C>T
NM_001258209.2:c.754C>T
NP_000181.2:p.Pro309Ser
NP_001019553.1:p.Pro292Ser
NP_001245137.1:p.Pro269Ser
NP_001245138.1:p.Pro252Ser
LRG_1076t1:c.925C>T
LRG_1076t2:c.874C>T
LRG_1076:g.13246C>T
LRG_1076p1:p.Pro309Ser
LRG_1076p2:p.Pro292Ser
NC_000011.9:g.118963832C>T
NC_000011.9:g.118963832C>T
NM_000190.3:c.925C>T

Protein change:

P252S

Links:

dbSNP: rs746707121

NCBI 1000 Genomes Browser:

rs746707121

Molecular consequence:

NM_000190.4:c.925C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001024382.2:c.874C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258208.2:c.805C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258209.2:c.754C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Acute intermittent porphyria (AIP)
Synonyms:: Porphobilinogen deaminase deficiency; Uroporphyrinogen synthase deficiency; UPS deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008294; MedGen: C0162565; Orphanet: 79276; OMIM: 176000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001265203	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Nov 8, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005042939	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001265203

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Nov 8, 2017)

germline

clinical testing

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

Citation Link,

SCV005042939

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease.

Chen B, Solis-Villa C, Hakenberg J, Qiao W, Srinivasan RR, Yasuda M, Balwani M, Doheny D, Peter I, Chen R, Desnick RJ.

Hum Mutat. 2016 Nov;37(11):1215-1222. doi: 10.1002/humu.23067. Epub 2016 Sep 5.

PubMed [citation]

PMID:: 27539938
PMCID:: PMC5063710

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001265203.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV005042939.1

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

Description

The missense variant c.925C>T p.Pro309Ser in the HMBS gene has been reported previously in an individual affected with Acute Intermittent Porphyria Chen et al., 2016. This variant is reported with the allele frequency 0.005% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/Likely Benign. However, study on multiple affected individuals and the functional impact of the variant is not available. The amino acid Proline at position 309 is changed to a Serine changing protein sequence and it might alter its composition and physico- chemical properties. The amino acid change p.Pro309Ser in HMBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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