NM_000143.4(FH):c.1430_1437dup (p.Ser480fs) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 31, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000199224.14

Allele description

NM_000143.4(FH):c.1430_1437dup (p.Ser480fs)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.1430_1437dup (p.Ser480fs)

HGVS:

NC_000001.11:g.241497925_241497932dup
NG_012338.1:g.26824_26831dup
NM_000143.4:c.1430_1437dupMANE SELECT
NP_000134.2:p.Ser480fs
NP_000134.2:p.Ser480fs
LRG_504t1:c.1430_1437dup
LRG_504:g.26824_26831dup
LRG_504p1:p.Ser480fs
NC_000001.10:g.241661223_241661224insTCCATTTT
NC_000001.10:g.241661225_241661232dup
NM_000143.3:c.1430_1437dup
NM_000143.3:c.1430_1437dupAAAATGGA
p.S480KfsX6

Protein change:

S480fs

Links:

dbSNP: rs863223994

NCBI 1000 Genomes Browser:

rs863223994

Molecular consequence:

NM_000143.4:c.1430_1437dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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PREDICTED: Puntigrus tetrazona component of oligomeric golgi complex 5 (cog5), t...
PREDICTED: Puntigrus tetrazona component of oligomeric golgi complex 5 (cog5), transcript variant X1, mRNA
gi|2085264908|ref|XM_043236900.1|

Nucleotide
Conserved Domain Links for Protein (Select 2085264909) (1)
Conserved Domains

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251463	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 31, 2019)	germline	clinical testing	Citation Link,
SCV000544242	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12772087, 9635293, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251463

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 31, 2019)

germline

clinical testing

Citation Link,

SCV000544242

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 31, 2023)

germline

clinical testing

PubMed (3)
[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

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.

Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B.

Am J Hum Genet. 2003 Jul;73(1):95-106. Epub 2003 May 22.

PubMed [citation]

PMID:: 12772087
PMCID:: PMC1180594

Molecular analysis and prenatal diagnosis of human fumarase deficiency.

Coughlin EM, Christensen E, Kunz PL, Krishnamoorthy KS, Walker V, Dennis NR, Chalmers RA, Elpeleg ON, Whelan D, Pollitt RJ, Ramesh V, Mandell R, Shih VE.

Mol Genet Metab. 1998 Apr;63(4):254-62.

PubMed [citation]

PMID:: 9635293

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000251463.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12772087, 29423582)

#	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 Invitae, SCV000544242.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Ser480Lysfs*6) in the FH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the FH protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12772087; Invitae). This variant is also known as 1300‚Äì1307dup8. ClinVar contains an entry for this variant (Variation ID: 214407). This variant disrupts a region of the FH protein in which other variant(s) (p.Trp500*) have been determined to be pathogenic (PMID: 9635293). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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 16, 2024

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