NM_000255.4(MMUT):c.278G>A (p.Arg93His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 22, 2024
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:: RCV000724019.10

Allele description [Variation Report for NM_000255.4(MMUT):c.278G>A (p.Arg93His)]

NM_000255.4(MMUT):c.278G>A (p.Arg93His)

Gene:

MMUT:methylmalonyl-CoA mutase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p12.3

Genomic location:

Preferred name:

NM_000255.4(MMUT):c.278G>A (p.Arg93His)

HGVS:

NC_000006.12:g.49459189C>T
NG_007100.1:g.8951G>A
NM_000255.4:c.278G>AMANE SELECT
NP_000246.2:p.Arg93His
NC_000006.11:g.49426902C>T
NM_000255.1:c.278G>A
NM_000255.3:c.278G>A
NP_000246.1:p.Arg93His
P22033:p.Arg93His

Protein change:

R93H; ARG93HIS

Links:

UniProtKB: P22033#VAR_004409; OMIM: 609058.0004; dbSNP: rs121918251

NCBI 1000 Genomes Browser:

rs121918251

Molecular consequence:

NM_000255.4:c.278G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000227077	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Jun 2, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000812438	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16490061, 1670635, 7912889, 16281286, 28492532
SCV004021797	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 24, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000227077

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Jun 2, 2014)

germline

clinical testing

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

Citation Link,

SCV000812438

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 22, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004021797

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 24, 2023)

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	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Three novel and six common mutations in 11 patients with methylmalonic acidemia.

Kobayashi A, Kakinuma H, Takahashi H.

Pediatr Int. 2006 Feb;48(1):1-4. Erratum in: Pediatr Int. 2007 Feb;49(1):122.

PubMed [citation]

PMID:: 16490061

Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut0 and mut- methylmalonic aciduria by interallelic complementation.

Raff ML, Crane AM, Jansen R, Ledley FD, Rosenblatt DS.

J Clin Invest. 1991 Jan;87(1):203-7.

PubMed [citation]

PMID:: 1670635
PMCID:: PMC295026

See all PubMed Citations (5)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227077.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	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		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000812438.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 93 of the MUT protein (p.Arg93His). This variant is present in population databases (rs121918251, gnomAD 0.04%). This missense change has been observed in individuals with methylmalonic aciduria (PMID: 1670635, 16281286, 16490061). ClinVar contains an entry for this variant (Variation ID: 1880). 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 MUT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MUT function (PMID: 1670635, 7912889, 16281286). For these reasons, this variant has been classified as 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

From GeneDx, SCV004021797.1

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

Description

Published functional studies demonstrate a damaging effect on propionate incorporation and protein function (Raff ML et al, 1991; Crane et al., 1994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33413471, 33726816, 1670635, 31523617, 31622506, 16281286, 7912889, 16490061)

#	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: Oct 13, 2024

ClinVar

Relating variation to medicine