NM_002454.3(MTRR):c.920dup (p.Tyr307Ter) AND Methylcobalamin deficiency type cblE

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 11, 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:: RCV002881842.2

Allele description [Variation Report for NM_002454.3(MTRR):c.920dup (p.Tyr307Ter)]

NM_002454.3(MTRR):c.920dup (p.Tyr307Ter)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

5p15.31

Genomic location:

Preferred name:

NM_002454.3(MTRR):c.920dup (p.Tyr307Ter)

HGVS:

NC_000005.10:g.7885717dup
NG_008856.1:g.21614dup
NG_008856.2:g.39860dup
NM_001364440.2:c.920dup
NM_001364441.2:c.920dup
NM_001364442.2:c.920dup
NM_002454.3:c.920dupMANE SELECT
NM_024010.4:c.920dup
NP_001351369.1:p.Tyr307Ter
NP_001351370.1:p.Tyr307Ter
NP_001351371.1:p.Tyr307Ter
NP_002445.2:p.Tyr307Ter
NP_076915.3:p.Tyr307Ter
NC_000005.9:g.7885829_7885830insA
NC_000005.9:g.7885830dup
NR_134480.2:n.999dup
NR_134481.2:n.1013dup
NR_134482.2:n.859dup
NR_157168.2:n.973dup
NR_157169.2:n.833dup
NR_157170.2:n.999dup
NR_157171.2:n.833dup
NR_157172.2:n.859dup
NR_157173.2:n.987dup
NR_157174.2:n.859dup
NR_157175.2:n.1013dup
NR_157176.2:n.1153dup
NR_157177.2:n.1008dup
NR_157178.2:n.1013dup

Protein change:

Y307*

Molecular consequence:

NR_134480.2:n.999dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134481.2:n.1013dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134482.2:n.859dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157168.2:n.973dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157169.2:n.833dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157170.2:n.999dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157171.2:n.833dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157172.2:n.859dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157173.2:n.987dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157174.2:n.859dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157175.2:n.1013dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157176.2:n.1153dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157177.2:n.1008dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157178.2:n.1013dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001364440.2:c.920dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001364441.2:c.920dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001364442.2:c.920dup - nonsense - [Sequence Ontology: SO:0001587]
NM_002454.3:c.920dup - nonsense - [Sequence Ontology: SO:0001587]
NM_024010.4:c.920dup - 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
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
SCV003241038	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 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

SCV003241038

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 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 Invitae, SCV003241038.2

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

Description

This sequence change creates a premature translational stop signal (p.Tyr307*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MTRR-related conditions. ClinVar contains an entry for this variant (Variation ID: 2035984). 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

Last Updated: Feb 28, 2024

ClinVar

Relating variation to medicine