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NM_000143.4(FH):c.431G>A (p.Gly144Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 17, 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:
RCV001022288.3

Allele description [Variation Report for NM_000143.4(FH):c.431G>A (p.Gly144Glu)]

NM_000143.4(FH):c.431G>A (p.Gly144Glu)

Gene:
FH:fumarate hydratase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q43
Genomic location:
Preferred name:
NM_000143.4(FH):c.431G>A (p.Gly144Glu)
HGVS:
  • NC_000001.11:g.241512091C>T
  • NG_012338.1:g.12664G>A
  • NM_000143.4:c.431G>AMANE SELECT
  • NP_000134.2:p.Gly144Glu
  • LRG_504t1:c.431G>A
  • LRG_504:g.12664G>A
  • NC_000001.10:g.241675391C>T
  • NC_000001.10:g.241675391C>T
  • NM_000143.3:c.431G>A
Protein change:
G144E
Links:
dbSNP: rs1057521425
NCBI 1000 Genomes Browser:
rs1057521425
Molecular consequence:
  • NM_000143.4:c.431G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001184003Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Oct 17, 2023) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

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

Citations

PubMed

Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase.

Ajalla Aleixo MA, Rangel VL, Rustiguel JK, de Pádua RAP, Nonato MC.

FEBS J. 2019 May;286(10):1925-1940. doi: 10.1111/febs.14782. Epub 2019 Mar 7.

PubMed [citation]
PMID:
30761759

Details of each submission

From Ambry Genetics, SCV001184003.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.G144E variant (also known as c.431G>A), located in coding exon 4 of the FH gene, results from a G to A substitution at nucleotide position 431. The glycine at codon 144 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been observed in at least one individual who has a personal or family history that is consistent with FH-associated disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on internal structural assessment, this alteration results in destabilization of the FH complex, near the substrate binding site (Ajalla Aleixo MA et al. FEBS J., 2019 May;286:1925-1940; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 29, 2024