VCV000523899.12 - ClinVar

NM_002454.3(MTRR):c.1780A>T (p.Arg594Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002454.3(MTRR):c.1780A>T (p.Arg594Ter)

Variation ID: 523899 Accession: VCV000523899.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5p15.31 5: 7897075 (GRCh38) [ NCBI UCSC ] 5: 7897188 (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	May 21, 2018	Apr 4, 2026	Oct 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002454.3:c.1780A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002445.2:p.Arg594Ter	nonsense
NM_001364440.2:c.1780A>T	NP_001351369.1:p.Arg594Ter	nonsense
NM_001364441.2:c.1780A>T	NP_001351370.1:p.Arg594Ter	nonsense
NM_001364442.2:c.1780A>T	NP_001351371.1:p.Arg594Ter	nonsense
NM_024010.4:c.1780A>T	NP_076915.3:p.Arg594Ter	nonsense
NR_134480.2:n.1859A>T		non-coding transcript variant
NR_134481.2:n.1784A>T		non-coding transcript variant
NR_134482.2:n.1719A>T		non-coding transcript variant
NR_157168.2:n.1833A>T		non-coding transcript variant
NR_157169.2:n.1693A>T		non-coding transcript variant
NR_157170.2:n.1859A>T		non-coding transcript variant
NR_157171.2:n.1716A>T		non-coding transcript variant
NR_157172.2:n.1630A>T		non-coding transcript variant
NR_157173.2:n.1870A>T		non-coding transcript variant
NR_157174.2:n.1871A>T		non-coding transcript variant
NR_157175.2:n.2025A>T		non-coding transcript variant
NR_157176.2:n.2188A>T		non-coding transcript variant
NR_157177.2:n.1868A>T		non-coding transcript variant
NR_157178.2:n.1896A>T		non-coding transcript variant
NC_000005.10:g.7897075A>T
NC_000005.9:g.7897188A>T
NG_008856.1:g.32972A>T

... more HGVS ... less HGVS

Protein change

R594*

Other names

Canonical SPDI

NC_000005.10:7897074:A:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA359159682 dbSNP: rs1293600145 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.
MTRR		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	1076	1298

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Apr 27, 2018	RCV000627375.1
Methylcobalamin deficiency type cblE	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 11, 2024	RCV001834982.8
Neural tube defects, folate-sensitive	Likely pathogenic (1)	criteria provided, single submitter	Mar 28, 2024	RCV003465365.2

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.	Expand all rows Collapse all rows 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 (Apr 27, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000748369.3 First in ClinVar: May 21, 2018 Last updated: May 21, 2018	Comment: show The R594X variant in the MTRR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R594X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R594X as a likely pathogenic variant. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Mar 28, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neural tube defects, folate-sensitive	Baylor Genetics Accession: SCV004196491.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (May 15, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Methylcobalamin deficiency type cblE	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002222784.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (1) PubMed: 15714522 Comment: show For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 523899). This variant has not been reported in the literature in individuals affected with MTRR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg594*) in the MTRR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTRR are known to be pathogenic (PMID: 15714522). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 11, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	CblE complementation type homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism	Natera, Inc. Accession: SCV002077218.2 First in ClinVar: Feb 13, 2022 Last updated: Apr 04, 2026	Comment: show The c.1780A>T variant in MTRR is a nonsense variant predicted to introduce a stop codon at amino acid 594. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The R594X variant in the MTRR gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R594X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R594X as a likely pathogenic variant.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 523899). This variant has not been reported in the literature in individuals affected with MTRR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg594*) in the MTRR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTRR are known to be pathogenic (PMID: 15714522).

Comment:

The c.1780A>T variant in MTRR is a nonsense variant predicted to introduce a stop codon at amino acid 594. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). Given the available evidence, this variant is classified as Likely Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.	Zavadáková P	Human mutation	2005	PMID: 15714522

Text-mined citations for rs1293600145 ...

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 Apr 04, 2026