NM_002454.3(MTRR):c.1780A>T (p.Arg594Ter) AND Methylcobalamin deficiency type cblE

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 15, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001834982.6

Allele description [Variation Report for NM_002454.3(MTRR):c.1780A>T (p.Arg594Ter)]

NM_002454.3(MTRR):c.1780A>T (p.Arg594Ter)

Gene:

MTRR:5-methyltetrahydrofolate-homocysteine methyltransferase reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p15.31

Genomic location:

Preferred name:

NM_002454.3(MTRR):c.1780A>T (p.Arg594Ter)

HGVS:

NC_000005.10:g.7897075A>T
NG_008856.1:g.32972A>T
NM_001364440.2:c.1780A>T
NM_001364441.2:c.1780A>T
NM_001364442.2:c.1780A>T
NM_002454.3:c.1780A>TMANE SELECT
NM_024010.4:c.1780A>T
NP_001351369.1:p.Arg594Ter
NP_001351370.1:p.Arg594Ter
NP_001351371.1:p.Arg594Ter
NP_002445.2:p.Arg594Ter
NP_076915.3:p.Arg594Ter
NC_000005.9:g.7897188A>T
NM_002454.2:c.1780A>T
NR_134480.2:n.1859A>T
NR_134481.2:n.1784A>T
NR_134482.2:n.1719A>T
NR_157168.2:n.1833A>T
NR_157169.2:n.1693A>T
NR_157170.2:n.1859A>T
NR_157171.2:n.1716A>T
NR_157172.2:n.1630A>T
NR_157173.2:n.1870A>T
NR_157174.2:n.1871A>T
NR_157175.2:n.2025A>T
NR_157176.2:n.2188A>T
NR_157177.2:n.1868A>T
NR_157178.2:n.1896A>T

Protein change:

R594*

Links:

dbSNP: rs1293600145

NCBI 1000 Genomes Browser:

rs1293600145

Molecular consequence:

NR_134480.2:n.1859A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134481.2:n.1784A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134482.2:n.1719A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157168.2:n.1833A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157169.2:n.1693A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157170.2:n.1859A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157171.2:n.1716A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157172.2:n.1630A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157173.2:n.1870A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157174.2:n.1871A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157175.2:n.2025A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157176.2:n.2188A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157177.2:n.1868A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157178.2:n.1896A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001364440.2:c.1780A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001364441.2:c.1780A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001364442.2:c.1780A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_002454.3:c.1780A>T - nonsense - [Sequence Ontology: SO:0001587]
NM_024010.4:c.1780A>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Methylcobalamin deficiency type cblE (HMAE)
Synonyms:: VITAMIN B12-RESPONSIVE HOMOCYSTINURIA, cblE TYPE; Homocystinuria-Megaloblastic anemia due to defect in cobalamin metabolism, cblE complementation type; HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblE COMPLEMENTATION TYPE; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009354; MedGen: C1856057; Orphanet: 2169; Orphanet: 622; OMIM: 236270

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002077218	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Aug 7, 2020)	germline	clinical testing
SCV002222784	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15714522, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002077218

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Aug 7, 2020)

germline

clinical testing

SCV002222784

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 15, 2023)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.

Zavadáková P, Fowler B, Suormala T, Novotna Z, Mueller P, Hennermann JB, Zeman J, Vilaseca MA, Vilarinho L, Gutsche S, Wilichowski E, Horneff G, Kozich V.

Hum Mutat. 2005 Mar;25(3):239-47. Erratum in: Hum Mutat. 2005 Dec;26(6):590.

PubMed [citation]

PMID:: 15714522

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 Natera, Inc., SCV002077218.1

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002222784.4

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 523899). This variant has not been reported in the literature in individuals affected with MTRR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg594*) in the MTRR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTRR are known to be pathogenic (PMID: 15714522).

#	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: Feb 16, 2025

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