NM_002454.3(MTRR):c.446C>T (p.Ala149Val) AND Methylcobalamin deficiency type cblE

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 22, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001081253.12

Allele description [Variation Report for NM_002454.3(MTRR):c.446C>T (p.Ala149Val)]

NM_002454.3(MTRR):c.446C>T (p.Ala149Val)

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.446C>T (p.Ala149Val)

HGVS:

NC_000005.10:g.7877988C>T
NG_008856.1:g.13885C>T
NM_001364440.2:c.446C>T
NM_001364441.2:c.446C>T
NM_001364442.2:c.446C>T
NM_002454.3:c.446C>TMANE SELECT
NM_024010.4:c.446C>T
NP_001351369.1:p.Ala149Val
NP_001351370.1:p.Ala149Val
NP_001351371.1:p.Ala149Val
NP_002445.2:p.Ala149Val
NP_076915.3:p.Ala149Val
NC_000005.9:g.7878101C>T
NM_002454.2:c.446C>T
NR_134480.2:n.525C>T
NR_134481.2:n.539C>T
NR_134482.2:n.385C>T
NR_157168.2:n.499C>T
NR_157169.2:n.359C>T
NR_157170.2:n.385C>T
NR_157171.2:n.359C>T
NR_157172.2:n.385C>T
NR_157173.2:n.513C>T
NR_157174.2:n.385C>T
NR_157175.2:n.539C>T
NR_157176.2:n.539C>T
NR_157177.2:n.534C>T
NR_157178.2:n.539C>T

Protein change:

A149V

Links:

dbSNP: rs142714881

NCBI 1000 Genomes Browser:

rs142714881

Molecular consequence:

NM_001364440.2:c.446C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001364441.2:c.446C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001364442.2:c.446C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002454.3:c.446C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024010.4:c.446C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_134480.2:n.525C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134481.2:n.539C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134482.2:n.385C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157168.2:n.499C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157169.2:n.359C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157170.2:n.385C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157171.2:n.359C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157172.2:n.385C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157173.2:n.513C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157174.2:n.385C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157175.2:n.539C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157176.2:n.539C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157177.2:n.534C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_157178.2:n.539C>T - 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

Recent activity

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ephrin-A5 isoform 2 precursor [Mus musculus]
ephrin-A5 isoform 2 precursor [Mus musculus]
gi|6753724|ref|NP_034239.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001042127	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 22, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003811480	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001042127

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 22, 2024)

germline

clinical testing

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

SCV003811480

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 19, 2022)

germline

clinical testing

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

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001042127.6

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

From Revvity Omics, Revvity, SCV003811480.2

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

Last Updated: Oct 8, 2024

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