NM_005957.5(MTHFR):c.476A>G (p.Asp159Gly) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 24, 2020
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:: RCV001260224.1

Allele description [Variation Report for NM_005957.5(MTHFR):c.476A>G (p.Asp159Gly)]

NM_005957.5(MTHFR):c.476A>G (p.Asp159Gly)

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.476A>G (p.Asp159Gly)

HGVS:

NC_000001.11:g.11800322T>C
NG_013351.1:g.10782A>G
NM_001330358.2:c.599A>G
NM_005957.5:c.476A>GMANE SELECT
NP_001317287.1:p.Asp200Gly
NP_005948.3:p.Asp159Gly
LRG_726:g.10782A>G
NC_000001.10:g.11860379T>C
p.Asp159Gly

Protein change:

D159G

Links:

dbSNP: rs1644355976

NCBI 1000 Genomes Browser:

rs1644355976

Molecular consequence:

NM_001330358.2:c.599A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.476A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

unknown functional consequence

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

Recent activity

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target of myb1-like protein 2 [Homo sapiens]
target of myb1-like protein 2 [Homo sapiens]
gi|18698597|gb|AAL78338.1|AF467441_

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001435289	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 24, 2020)	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

SCV001435289

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 24, 2020)

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
Hindu	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV001435289.1

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

Description

A heterozygous missense variation in exon 3 of the MTHFR gene that results in the amino acid substitution of Glycine for Aspartic acid at codon 159 was detected. The observed variant c.476A>G (p.Asp159Gly) lies in the methylenetetrahydrofolate reductase domain of the MTHFR protein and has previously been reported at a nearby position (c.474A>T; p.G158G) in a homozygous state, in patients affected with homocystinuria (Ben-Shachar et al. 2012). The variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.

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

Last Updated: Jun 23, 2024

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