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NM_002454.3(MTRR):c.1361C>T (p.Ser454Leu) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 4, 2017
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:
RCV000757493.10

Allele description [Variation Report for NM_002454.3(MTRR):c.1361C>T (p.Ser454Leu)]

NM_002454.3(MTRR):c.1361C>T (p.Ser454Leu)

Gene:
MTRR:5-methyltetrahydrofolate-homocysteine methyltransferase reductase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5p15.31
Genomic location:
Preferred name:
NM_002454.3(MTRR):c.1361C>T (p.Ser454Leu)
HGVS:
  • NC_000005.10:g.7891405C>T
  • NG_008856.1:g.27302C>T
  • NM_001364440.2:c.1361C>T
  • NM_001364441.2:c.1361C>T
  • NM_001364442.2:c.1361C>T
  • NM_002454.3:c.1361C>TMANE SELECT
  • NM_024010.4:c.1361C>T
  • NP_001351369.1:p.Ser454Leu
  • NP_001351370.1:p.Ser454Leu
  • NP_001351371.1:p.Ser454Leu
  • NP_002445.2:p.Ser454Leu
  • NP_076915.3:p.Ser454Leu
  • NC_000005.9:g.7891518C>T
  • NC_000005.9:g.7891518C>T
  • NM_002454.2:c.1361C>T
  • NR_134480.2:n.1440C>T
  • NR_134481.2:n.1365C>T
  • NR_134482.2:n.1300C>T
  • NR_157168.2:n.1414C>T
  • NR_157169.2:n.1274C>T
  • NR_157170.2:n.1440C>T
  • NR_157171.2:n.1297C>T
  • NR_157172.2:n.1211C>T
  • NR_157173.2:n.1451C>T
  • NR_157174.2:n.1452C>T
  • NR_157175.2:n.1606C>T
  • NR_157176.2:n.1769C>T
  • NR_157177.2:n.1449C>T
  • NR_157178.2:n.1477C>T
Protein change:
S454L; SER454LEU
Links:
OMIM: 602568.0007; dbSNP: rs137853062
NCBI 1000 Genomes Browser:
rs137853062
Molecular consequence:
  • NM_001364440.2:c.1361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364441.2:c.1361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001364442.2:c.1361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002454.3:c.1361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024010.4:c.1361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_134480.2:n.1440C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_134481.2:n.1365C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_134482.2:n.1300C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157168.2:n.1414C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157169.2:n.1274C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157170.2:n.1440C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157171.2:n.1297C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157172.2:n.1211C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157173.2:n.1451C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157174.2:n.1452C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157175.2:n.1606C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157176.2:n.1769C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157177.2:n.1449C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_157178.2:n.1477C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000885741ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Pathogenic
(Dec 4, 2017) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885741.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.Ser454Leu (rs137853062) has been reported in numerous patients with megaloblastic anemia and homocystinuria both as homozygotes or bi-allelic with the MTRR frameshift variant, p.Glu560fs (Ruiz-Mercado, 2016 and Vilaseca, 2003). Functional cell-based experiments from patient fibroblasts demonstrated elevated oxidative stress and apoptosis (Richard, 2013). Furthermore, methionine synthesis was normalized through expression of a wildtype copy of MTRR in fibroblasts cells of two homozygote patients (Zavadakova, 2005). This variant is listed in the Genome Aggregation Database (gnomAD) identified on a single chromosome out of 30,542, and has been reported to the ClinVar database as a pathogenic variant (Variation ID: 7033). The serine at position 454 is highly conserved up to baker’s yeast considering 15 species (Alamut v2.10) and computational analyses of the p.Ser454Leu variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Given the current evidence, the p.Ser454Leu is considered to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024