NM_002454.3(MTRR):c.283+1_283+20del AND Homocystinuria-Megaloblastic anemia due to defect in cobalamin metabolism, cblE complementation type

Clinical significance:Likely pathogenic (Last evaluated: Jul 11, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001204859.2

Allele description [Variation Report for NM_002454.3(MTRR):c.283+1_283+20del]

NM_002454.3(MTRR):c.283+1_283+20del

Gene:
MTRR:5-methyltetrahydrofolate-homocysteine methyltransferase reductase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
5p15.31
Genomic location:
Preferred name:
NM_002454.3(MTRR):c.283+1_283+20del
HGVS:
  • NC_000005.10:g.7873527_7873546del
  • NG_008856.1:g.9424_9443del
  • NG_033101.1:g.493_512del
  • NM_001364440.2:c.283+1_283+20del
  • NM_001364441.2:c.283+1_283+20del
  • NM_001364442.2:c.283+1_283+20del
  • NM_002454.3:c.283+1_283+20delMANE SELECT
  • NM_024010.4:c.283+1_283+20del
  • NC_000005.9:g.7873639_7873658del
  • NC_000005.9:g.7873640_7873659del
  • NM_002454.2:c.283+1_283+20del
Links:
Molecular consequence:
  • NM_001364440.2:c.283+1_283+20del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001364441.2:c.283+1_283+20del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001364442.2:c.283+1_283+20del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_002454.3:c.283+1_283+20del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_024010.4:c.283+1_283+20del - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001376086Invitaecriteria provided, single submitter
Likely pathogenic
(Jul 11, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

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
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001376086.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change affects a donor splice site in intron 3 of the MTRR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MTRR-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MTRR are known to be pathogenic (PMID: 15714522). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 10, 2021

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