VCV000446306.11 - ClinVar

NM_005956.4(MTHFD1):c.146C>T (p.Ser49Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005956.4(MTHFD1):c.146C>T (p.Ser49Phe)

Variation ID: 446306 Accession: VCV000446306.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q23.3 14: 64411109 (GRCh38) [ NCBI UCSC ] 14: 64877827 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 27, 2017	Feb 14, 2024	Jan 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005956.4:c.146C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005947.3:p.Ser49Phe	missense
NM_001364837.1:c.146C>T	NP_001351766.1:p.Ser49Phe	missense
NC_000014.9:g.64411109C>T
NC_000014.8:g.64877827C>T
NG_012450.2:g.28069C>T
LRG_1243:g.28069C>T
LRG_1243t1:c.146C>T	LRG_1243p1:p.Ser49Phe

... more HGVS ... less HGVS

Protein change

S49F

Other names

Canonical SPDI

NC_000014.9:64411108:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00011

Trans-Omics for Precision Medicine (TOPMed) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00013

Exome Aggregation Consortium (ExAC) 0.00015

Links

ClinGen: CA7225850 OMIM: 172460.0007 dbSNP: rs370444838 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MTHFD1		-	-	GRCh38 GRCh37	397	497

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 15, 2018	RCV000515546.6
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2024	RCV001380971.5
Severe combined immunodeficiency disease	Pathogenic (1)	criteria provided, single submitter	Nov 3, 2021	RCV001797742.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Oct 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000883292.1 First in ClinVar: Nov 27, 2017 Last updated: Nov 27, 2017	Publications: PubMed (1) PubMed: 25633902 Comment: 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: … (more) 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: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/25633902). 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/25633902). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PM2-Supporting => PM2 downgraded in strength to Supporting. (less)
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Severe combined immunodeficiency disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002041696.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021	Publications: PubMed (4) PubMed: 31589614‚ 32414565‚ 25633902‚ 27707659 Comment: Variant summary: MTHFD1 c.146C>T (p.Ser49Phe) results in a non-conservative amino acid change located in the Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain (IPR020630) of the encoded protein sequence. … (more) Variant summary: MTHFD1 c.146C>T (p.Ser49Phe) results in a non-conservative amino acid change located in the Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain (IPR020630) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251122 control chromosomes (gnomAD v2.1, exomes dataset). This frequency is not higher than the maximum expected for a pathogenic variant in MTHFD1 causing Severe Combined Immunodeficiency Syndrome (0.00035), allowing no conclusion about variant significance. c.146C>T has been reported in the literature in at least 5 individuals from two families who were affected with combined immunodeficiency and megaloblastic anemia (Burda_2015, Bidla_2020), of note the variant co-segregated with disease in these families. These data indicate that the variant is likely to be associated with disease. Publications also reports experimental evidence evaluating an impact on protein function, and demonstrated severely decreased enzyme activity in patient derived fibroblast (Burda_2015, Bidla_2020). Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001530409.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 18, 2023
Pathogenic (Jan 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001579206.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 25633902‚ 32414565 Comment: This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the MTHFD1 protein (p.Ser49Phe). … (more) This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the MTHFD1 protein (p.Ser49Phe). This variant is present in population databases (rs370444838, gnomAD 0.02%). This missense change has been observed in individual(s) with methylenetetrahydrofolate dehydrogenase 1 deficiency (PMID: 25633902, 32414565). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 446306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTHFD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 12, 2020)	no assertion criteria provided Method: literature only	COMBINED IMMUNODEFICIENCY AND MEGALOBLASTIC ANEMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000611635.2 First in ClinVar: Nov 27, 2017 Last updated: Aug 17, 2020	Publications: PubMed (3) PubMed: 25633902‚ 32414565‚ 23402911 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2017. Baltimore, Md. Comment on evidence: In 3 patients from a nonconsanguineous Swedish family with combined immunodeficiency and megaloblastic anemia, Burda et al. (2015) identified compound heterozygous mutations in the MTHFD1 … (more) In 3 patients from a nonconsanguineous Swedish family with combined immunodeficiency and megaloblastic anemia, Burda et al. (2015) identified compound heterozygous mutations in the MTHFD1 gene: a c.146C-T transition, resulting in a ser49-to-phe (S49F) substitution, and a c.673G-T transversion, resulting in a glu225-to-ter (E225X; 172460.0008) substitution. Hamosh (2017) noted that the S49F variant was reported in 34 of 276,866 alleles in the gnomAD database (11/13/2017) for a European allele frequency of .0002368. The E225X variant was reported in heterozygous state in 4 of 246,264 alleles for an allele frequency of 1.624 x 10(-5). All 4 alleles were found in non-Finnish Europeans. In a 34-year-old woman with CIMAH, Bidla et al. (2020) identified compound heterozygous mutations in the MTHFD1 gene: S49F, affecting a highly conserved residue in the NADP-binding site of the dehydrogenase/cyclohydrolase catalytic site, and a c.826G-C transversion, resulting in a gly276-to-arg (G276R; 172460.0011) substitution at a highly conserved residue in the dehydrogenase catalytic site. The mutations were found by whole-exome sequencing. The patient's affected brother also carried both mutations. The mother was a carrier for the G276R mutation; the father was not available for testing. Studies in patient fibroblasts showed reduction in MTHFD1 protein expression and absence of MTHFD1 enzyme activity. The G276R variant was not present in the gnomAD database. The patient was originally reported by Chery et al. (2013). (less)

Comment:

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: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/25633902). 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/25633902). PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/25633902). PM2-Supporting => PM2 downgraded in strength to Supporting.

Comment:

Variant summary: MTHFD1 c.146C>T (p.Ser49Phe) results in a non-conservative amino acid change located in the Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain (IPR020630) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251122 control chromosomes (gnomAD v2.1, exomes dataset). This frequency is not higher than the maximum expected for a pathogenic variant in MTHFD1 causing Severe Combined Immunodeficiency Syndrome (0.00035), allowing no conclusion about variant significance. c.146C>T has been reported in the literature in at least 5 individuals from two families who were affected with combined immunodeficiency and megaloblastic anemia (Burda_2015, Bidla_2020), of note the variant co-segregated with disease in these families. These data indicate that the variant is likely to be associated with disease. Publications also reports experimental evidence evaluating an impact on protein function, and demonstrated severely decreased enzyme activity in patient derived fibroblast (Burda_2015, Bidla_2020). Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 49 of the MTHFD1 protein (p.Ser49Phe). This variant is present in population databases (rs370444838, gnomAD 0.02%). This missense change has been observed in individual(s) with methylenetetrahydrofolate dehydrogenase 1 deficiency (PMID: 25633902, 32414565). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 446306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MTHFD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency.	Bidla G	Molecular genetics and metabolism	2020	PMID: 32414565
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency.	Ramakrishnan KA	The journal of allergy and clinical immunology. In practice	2016	PMID: 27707659
Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.	Burda P	Journal of inherited metabolic disease	2015	PMID: 25633902
Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant.	Chery C	Biochimie	2013	PMID: 23402911
Hamosh, A. Personal Communication. 2017. Baltimore, Md.	-	-	-	-

Text-mined citations for rs370444838 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005956.4(MTHFD1):c.146C>T (p.Ser49Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs370444838 ...