NM_005956.4(MTHFD1):c.517C>T (p.Arg173Cys) AND Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Oct 15, 2018
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:: RCV000515545.2

Allele description [Variation Report for NM_005956.4(MTHFD1):c.517C>T (p.Arg173Cys)]

NM_005956.4(MTHFD1):c.517C>T (p.Arg173Cys)

Gene:

MTHFD1:methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q23.3

Genomic location:

Preferred name:

NM_005956.4(MTHFD1):c.517C>T (p.Arg173Cys)

HGVS:

NC_000014.9:g.64417926C>T
NG_012450.2:g.34886C>T
NM_001364837.1:c.517C>T
NM_005956.4:c.517C>TMANE SELECT
NP_001351766.1:p.Arg173Cys
NP_005947.3:p.Arg173Cys
LRG_1243t1:c.517C>T
LRG_1243:g.34886C>T
LRG_1243p1:p.Arg173Cys
NC_000014.8:g.64884644C>T
NG_012450.1:g.34886C>T
NM_005956.3:c.517C>T

Protein change:

R173C; ARG173CYS

Links:

OMIM: 172460.0004; dbSNP: rs141210410

NCBI 1000 Genomes Browser:

rs141210410

Molecular consequence:

NM_001364837.1:c.517C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005956.4:c.517C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
Synonyms:: METHYLENETETRAHYDROFOLATE DEHYDROGENASE 1 DEFICIENCY; COMBINED IMMUNODEFICIENCY AND MEGALOBLASTIC ANEMIA
Identifiers:: MONDO: MONDO:0060611; MedGen: C4540434; OMIM: 617780

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000611632	OMIM	no assertion criteria provided	Pathogenic (Nov 21, 2017)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000883251	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 15, 2018)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 21813566, 25741868
SCV001133188	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Sep 26, 2019)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000611632

OMIM

no assertion criteria provided

Pathogenic
(Nov 21, 2017)

germline

literature only

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

SCV000883251

SIB Swiss Institute of Bioinformatics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 15, 2018)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

SCV001133188

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

no assertion criteria provided

Pathogenic
(Sep 26, 2019)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.

Watkins D, Schwartzentruber JA, Ganesh J, Orange JS, Kaplan BS, Nunez LD, Majewski J, Rosenblatt DS.

J Med Genet. 2011 Sep;48(9):590-2. doi: 10.1136/jmedgenet-2011-100286. Epub 2011 Aug 3.

PubMed [citation]

PMID:: 21813566

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 OMIM, SCV000611632.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the c.517C-T transition in the MTHFD1 gene, resulting in an arg173-to-cys (R173C) substitution, that was found in compound heterozygous state in a patient with combined immunodeficiency and megaloblastic anemia with hyperhomocysteinemia (CIMAH; 617780) by Watkins et al. (2011), see 172460.0003.

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

From SIB Swiss Institute of Bioinformatics, SCV000883251.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as Likely Pathogenic, for Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/21813566). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/21813566). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation(https://www.uniprot.org/uniprot/P11586).

#	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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001133188.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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