NM_000190.4(HMBS):c.754G>C (p.Ala252Pro) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 14, 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:: RCV002254508.8

Allele description [Variation Report for NM_000190.4(HMBS):c.754G>C (p.Ala252Pro)]

NM_000190.4(HMBS):c.754G>C (p.Ala252Pro)

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.754G>C (p.Ala252Pro)

Other names:

p.Ala252Pro

HGVS:

NC_000011.10:g.119092506G>C
NG_008093.1:g.12630G>C
NM_000190.4:c.754G>CMANE SELECT
NM_001024382.2:c.703G>C
NM_001258208.2:c.652-252G>C
NM_001258209.2:c.601-252G>C
NP_000181.2:p.Ala252Pro
NP_001019553.1:p.Ala235Pro
LRG_1076t1:c.754G>C
LRG_1076t2:c.703G>C
LRG_1076:g.12630G>C
LRG_1076p1:p.Ala252Pro
LRG_1076p2:p.Ala235Pro
NC_000011.9:g.118963216G>C

Protein change:

A235P

Links:

dbSNP: rs118204113

NCBI 1000 Genomes Browser:

rs118204113

Molecular consequence:

NM_001258208.2:c.652-252G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001258209.2:c.601-252G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000190.4:c.754G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024382.2:c.703G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002525807	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 28, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17298216, 9067752, 25741868
SCV004294972	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8262523, 9067752, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002525807

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 28, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004294972

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 14, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

May 2006 update in porphobilinogen deaminase gene polymorphisms and mutations causing acute intermittent porphyria: comparison with the situation in Slavic population.

Hrdinka M, Puy H, Martasek P.

Physiol Res. 2006;55 Suppl 2:S119-136. Review.

PubMed [citation]

PMID:: 17298216

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

See all PubMed Citations (5)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV002525807.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

PP1, PP3, PP4, PM2, PM5

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294972.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 252 of the HMBS protein (p.Ala252Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with acute intermittent porphyria (PMID: 9067752; Invitae). ClinVar contains an entry for this variant (Variation ID: 1691435). 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. This variant disrupts the p.Ala252 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been observed in individuals with HMBS-related conditions (PMID: 8262523, 9067752), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Sep 29, 2024

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