NM_005957.5(MTHFR):c.760C>T (p.Pro254Ser) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 9, 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:: RCV000167601.5

Allele description [Variation Report for NM_005957.5(MTHFR):c.760C>T (p.Pro254Ser)]

NM_005957.5(MTHFR):c.760C>T (p.Pro254Ser)

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.760C>T (p.Pro254Ser)

HGVS:

NC_000001.11:g.11796226G>A
NG_013351.1:g.14878C>T
NM_001330358.2:c.883C>T
NM_005957.5:c.760C>TMANE SELECT
NP_001317287.1:p.Pro295Ser
NP_005948.3:p.Pro254Ser
NP_005948.3:p.Pro254Ser
LRG_726t1:c.760C>T
LRG_726:g.14878C>T
LRG_726p1:p.Pro254Ser
NC_000001.10:g.11856283G>A
NM_005957.4:c.760C>T
P42898:p.Pro254Ser

Protein change:

P254S

Links:

UniProtKB: P42898#VAR_074132; dbSNP: rs786204017

NCBI 1000 Genomes Browser:

rs786204017

Molecular consequence:

NM_001330358.2:c.883C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005957.5:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000218482	University Children's Hospital, University of Zurich	no assertion criteria provided (Clinical disease; enzymatic activity/kinetics in patient fibroblasts)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002116853	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 9, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25736335, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218482

University Children's Hospital, University of Zurich

no assertion criteria provided

(Clinical disease; enzymatic activity/kinetics in patient fibroblasts)

Pathogenic

germline

clinical testing

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

SCV002116853

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 9, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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	clinical testing

Citations

PubMed

Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients.

Burda P, Schäfer A, Suormala T, Rummel T, Bürer C, Heuberger D, Frapolli M, Giunta C, Sokolová J, Vlášková H, Kožich V, Koch HG, Fowler B, Froese DS, Baumgartner MR.

Hum Mutat. 2015 Jun;36(6):611-21. doi: 10.1002/humu.22779. Epub 2015 Apr 27.

PubMed [citation]

PMID:: 25736335

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

Details of each submission

From University Children's Hospital, University of Zurich, SCV000218482.1

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002116853.3

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

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 254 of the MTHFR protein (p.Pro254Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 187881). This missense change has been observed in individual(s) with MTHFR deficiency (PMID: 25736335). This variant is not present in population databases (gnomAD no frequency).

#	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

Last Updated: Sep 29, 2024

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