NM_000190.4(HMBS):c.636G>A (p.Met212Ile) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 18, 2022
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:: RCV001056264.11

Allele description [Variation Report for NM_000190.4(HMBS):c.636G>A (p.Met212Ile)]

NM_000190.4(HMBS):c.636G>A (p.Met212Ile)

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.636G>A (p.Met212Ile)

HGVS:

NC_000011.10:g.119092148G>A
NG_008093.1:g.12272G>A
NM_000190.4:c.636G>AMANE SELECT
NM_001024382.2:c.585G>A
NM_001258208.2:c.636G>A
NM_001258209.2:c.585G>A
NP_000181.2:p.Met212Ile
NP_001019553.1:p.Met195Ile
NP_001245137.1:p.Met212Ile
NP_001245138.1:p.Met195Ile
LRG_1076t1:c.636G>A
LRG_1076t2:c.585G>A
LRG_1076:g.12272G>A
LRG_1076p1:p.Met212Ile
LRG_1076p2:p.Met195Ile
NC_000011.9:g.118962858G>A
NM_000190.3:c.636G>A

Protein change:

M195I

Links:

dbSNP: rs1219587773

NCBI 1000 Genomes Browser:

rs1219587773

Molecular consequence:

NM_000190.4:c.636G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001024382.2:c.585G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258208.2:c.636G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258209.2:c.585G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Homologene neighbors for GEO Profiles (Select 125836974) (0)
GEO Profiles
Protein Links for Nucleotide (Select 2540736113) (25)
Protein
Assembly for Nucleotide (Select 2540736119) (1)
Assembly
MAG: uncultured Methanobrevibacter sp. isolate RUG14734, whole genome shotgun se...
MAG: uncultured Methanobrevibacter sp. isolate RUG14734, whole genome shotgun sequence
gi|2540736133|ref|NZ_CADCKP01000005

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001220698	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 13, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002549477	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 18, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001220698

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 13, 2021)

germline

clinical testing

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

SCV002549477

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 18, 2022)

germline

clinical testing

Citation Link

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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001220698.5

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

Description

This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of porphyria (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Met212 amino acid residue in HMBS. Other variant(s) that disrupt this residue have been observed in individuals with HMBS-related conditions (PMID:¬†10602775), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces methionine with isoleucine at codon 212 of the HMBS protein (p.Met212Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine.

#	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 GeneDx, SCV002549477.2

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	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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