NM_005957.5(MTHFR):c.1793T>G (p.Leu598Arg) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 3, 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:: RCV001808247.1

Allele description [Variation Report for NM_005957.5(MTHFR):c.1793T>G (p.Leu598Arg)]

NM_005957.5(MTHFR):c.1793T>G (p.Leu598Arg)

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.1793T>G (p.Leu598Arg)

HGVS:

NC_000001.11:g.11790858A>C
NG_013351.1:g.20246T>G
NM_001330358.2:c.1916T>G
NM_005957.5:c.1793T>GMANE SELECT
NP_001317287.1:p.Leu639Arg
NP_005948.3:p.Leu598Arg
LRG_726:g.20246T>G
NC_000001.10:g.11850915A>C

Protein change:

L598R

Links:

dbSNP: rs786204034

NCBI 1000 Genomes Browser:

rs786204034

Molecular consequence:

NM_001330358.2:c.1916T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.1793T>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002058874	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:25736335

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002058874

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 3, 2022)

germline

clinical testing

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

PMID:25736335

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	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 3billion, SCV002058874.1

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

Description

A different missense change at the same codon (p.Leu598Pro) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000187902, PMID:25736335, PM5_M). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.761, PP3_P). A missense variant is a common mechanism associated with Homocystinuria due to MTHFR deficiency (PP2_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Jun 23, 2024

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