NM_005957.5(MTHFR):c.1011G>T (p.Gly337=) AND Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 15, 2023
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:: RCV004577963.1

Allele description [Variation Report for NM_005957.5(MTHFR):c.1011G>T (p.Gly337=)]

NM_005957.5(MTHFR):c.1011G>T (p.Gly337=)

Gene:

MTHFR:methylenetetrahydrofolate reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Preferred name:

NM_005957.5(MTHFR):c.1011G>T (p.Gly337=)

HGVS:

NC_000001.11:g.11795118C>A
NG_013351.1:g.15986G>T
NM_001330358.2:c.1134G>T
NM_001410750.1:c.1131G>T
NM_005957.5:c.1011G>TMANE SELECT
NP_001317287.1:p.Gly378=
NP_001397679.1:p.Gly377=
NP_005948.3:p.Gly337=
NP_005948.3:p.Gly337=
LRG_726t1:c.1011G>T
LRG_726:g.15986G>T
LRG_726p1:p.Gly337=
NC_000001.10:g.11855175C>A
NM_005957.4:c.1011G>T

Molecular consequence:

NM_001330358.2:c.1134G>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001410750.1:c.1131G>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_005957.5:c.1011G>T - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

effect on RNA splicing [Variation Ontology: 0362]

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
SCV004190229	Newborn Screening Center, Zibo Maternal and Child Health Care Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 15, 2023)	maternal, not applicable	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004190229

Newborn Screening Center, Zibo Maternal and Child Health Care Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 15, 2023)

maternal, not applicable

research

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
not provided	maternal	yes	1	not provided	not provided	not provided	not provided	research
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	research

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 Newborn Screening Center, Zibo Maternal and Child Health Care Hospital, SCV004190229.1

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

Description

Two compound heterozygous variations were present in this patient: this novel synonymous variant c.1011G>T and a previously documented variant c.154C>T (VCV000522696.5).

Description

This synonymous variant c.1011G>T (p.G337G) was observed in a male newborn that clinically diagnosed with homocystinuria. RNA-seq revealed that c.1011G>T caused an out-of-frame deletion of 22 bp in exon 6 of MTHFR gene resulting in a premature termination codon (p.G337Gfs*57) . This variant is present in population databases (1000 Genome:.; ExAC:.; gnomAD:.). A nonsense pathogenic variant c.154C>T (p.R52*) was detected in trans in this patient. The patient's clinical phenotype was highly specific for gene. For these reasons, this variant has been classified as likely Pathogenic (PS3, PM3, PM2_PP, PP4).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided
2	not applicable	not applicable	not provided	whole blood	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 7, 2024

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