NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Benign (6 submissions)
Last evaluated:: Mar 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001197542.23

Allele description [Variation Report for NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)]

NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)

Gene:

MTHFR:methylenetetrahydrofolate reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.22

Genomic location:

Preferred name:

NM_005957.5(MTHFR):c.1286A>C (p.Glu429Ala)

Other names:

MTHFR, 1298A-C, GLU429ALA (rs1801131); E429A

HGVS:

NC_000001.11:g.11794419T>G
NG_013351.1:g.16685A>C
NM_001330358.2:c.1409A>C
NM_005957.5:c.1286A>CMANE SELECT
NP_001317287.1:p.Glu470Ala
NP_005948.3:p.Glu429Ala
NP_005948.3:p.Glu429Ala
LRG_726t1:c.1286A>C
LRG_726:g.16685A>C
LRG_726p1:p.Glu429Ala
NC_000001.10:g.11854476T>G
NM_005957.4:c.1286A>C
P42898:p.Glu429Ala

Protein change:

E470A; GLU429ALA

Links:

Genetic Testing Registry (GTR): GTR000593372; Genetic Testing Registry (GTR): GTR000613302; PharmGKB Clinical Annotation: 1183705832; UniProtKB: P42898#VAR_014882; OMIM: 607093.0004; dbSNP: rs1801131

NCBI 1000 Genomes Browser:

rs1801131

Molecular consequence:

NM_001330358.2:c.1409A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.1286A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Homocystinuria due to methylene tetrahydrofolate reductase deficiency
Synonyms:: HOMOCYSTINURIA DUE TO DEFICIENCY OF N(5,10)-METHYLENETETRAHYDROFOLATE REDUCTASE ACTIVITY; Homocysteinemia due to MTHFR deficiency; Homocysteinemia due to methylenetetrahydro-folate reductase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009353; MedGen: C1856061; Orphanet: 395; OMIM: 236250

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Burkholderia multivorans strain DDS 15A-1 chromosome 2, complete sequence
Burkholderia multivorans strain DDS 15A-1 chromosome 2, complete sequence
gi|685685000|gnl|LANL|DM80.Contig50 CP008729.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001455754	Natera, Inc.	no assertion criteria provided	Benign (Sep 16, 2020)	germline	clinical testing
SCV001733272	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001748535	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jul 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002506414	Institute of Human Genetics, University Hospital Muenster	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Dec 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9545395, 28514598, 25741868
SCV004805343	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Mar 25, 2024)	germline	research	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	yes	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

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ.

Am J Hum Genet. 1998 May;62(5):1044-51.

PubMed [citation]

PMID:: 9545395
PMCID:: PMC1377082

See all PubMed Citations (4)

Details of each submission

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001368321.2

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

Description

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in homozygous state.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001455754.1

#	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, SCV001733272.3

#	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 Genome-Nilou Lab, SCV001748535.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University Hospital Muenster, SCV002506414.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

ACMG categories: BA1, BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	blood	not provided		1	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805343.2

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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001368321	Centre for Mendelian Genomics, University Medical Centre Ljubljana	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: Likely pathogenic classification is not possible if no criteria are applicable. (ACMG Guidelines, 2015)	Likely pathogenic (Jan 28, 2019)	unknown	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

SCV001368321

Centre for Mendelian Genomics, University Medical Centre Ljubljana

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: Likely pathogenic classification is not possible if no criteria are applicable.

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 28, 2019)

unknown

clinical testing

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

Last Updated: Nov 10, 2024

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