NM_002454.3(MTRR):c.1418_1419del (p.Val473fs) AND Methylcobalamin deficiency type cblE

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 10, 2022
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:: RCV003091956.3

Allele description [Variation Report for NM_002454.3(MTRR):c.1418_1419del (p.Val473fs)]

NM_002454.3(MTRR):c.1418_1419del (p.Val473fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

5p15.31

Genomic location:

Preferred name:

NM_002454.3(MTRR):c.1418_1419del (p.Val473fs)

HGVS:

NC_000005.10:g.7892772TG[1]
NG_008856.2:g.46915TG[1]
NM_001364440.2:c.1418_1419del
NM_001364441.2:c.1418_1419del
NM_001364442.2:c.1418_1419del
NM_002454.3:c.1418_1419delMANE SELECT
NM_024010.4:c.1418_1419del
NP_001351369.1:p.Val473fs
NP_001351370.1:p.Val473fs
NP_001351371.1:p.Val473fs
NP_002445.2:p.Val473fs
NP_076915.3:p.Val473fs
NC_000005.9:g.7892885TG[1]
NC_000005.9:g.7892885_7892886del
NG_008856.1:g.28669TG[1]
NR_134480.2:n.1495TG[1]
NR_134481.2:n.1420TG[1]
NR_134482.2:n.1355TG[1]
NR_157168.2:n.1469TG[1]
NR_157169.2:n.1329TG[1]
NR_157170.2:n.1495TG[1]
NR_157171.2:n.1352TG[1]
NR_157172.2:n.1266TG[1]
NR_157173.2:n.1506TG[1]
NR_157174.2:n.1507TG[1]
NR_157175.2:n.1661TG[1]
NR_157176.2:n.1824TG[1]
NR_157177.2:n.1504TG[1]
NR_157178.2:n.1532TG[1]

Protein change:

V473fs

Molecular consequence:

NM_001364440.2:c.1418_1419del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001364441.2:c.1418_1419del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001364442.2:c.1418_1419del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002454.3:c.1418_1419del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024010.4:c.1418_1419del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_134480.2:n.1495TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134481.2:n.1420TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134482.2:n.1355TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157168.2:n.1469TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157169.2:n.1329TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157170.2:n.1495TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157171.2:n.1352TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157172.2:n.1266TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157173.2:n.1506TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157174.2:n.1507TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157175.2:n.1661TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157176.2:n.1824TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157177.2:n.1504TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157178.2:n.1532TG[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV003481063	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 10, 2022)	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

SCV003481063

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 10, 2022)

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003481063.2

#	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. 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.Val473Glyfs*37) 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: Oct 8, 2024

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