VCV002573279.3 - ClinVar

NM_000143.4(FH):c.490del (p.Met164fs)

Germline

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.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000143.4(FH):c.490del (p.Met164fs)

Variation ID: 2573279 Accession: VCV002573279.3

Type and length

Deletion, 1 bp

Location

Cytogenetic: 1q43 1: 241512032 (GRCh38) [ NCBI UCSC ] 1: 241675332 (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	Jul 29, 2023	Feb 14, 2024	Nov 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000143.4:c.490del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000134.2:p.Met164fs	frameshift
NC_000001.11:g.241512034del
NC_000001.10:g.241675334del
NG_012338.1:g.12723del
LRG_504:g.12723del
LRG_504t1:c.488del	LRG_504p1:p.Met164Cysfs

... more HGVS ... less HGVS

Protein change

M164fs

Other names

Canonical SPDI

NC_000001.11:241512031:TTT:TT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Links

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.
FH		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2036	2122

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.
Hereditary leiomyomatosis and renal cell cancer	Pathogenic (1)	criteria provided, single submitter	Feb 16, 2023	RCV003316968.2
Fumarase deficiency	Likely pathogenic (1)	criteria provided, single submitter	Feb 16, 2023	RCV003466053.1
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2023	RCV003575074.2

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.	More information 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.
Pathogenic (Feb 16, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Hereditary leiomyomatosis and renal cell cancer Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018069.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Likely pathogenic (Feb 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fumarase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004197376.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Nov 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004338236.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 11865300‚ 21398687 Comment: This sequence change creates a premature translational stop signal (p.Met164Cysfs2) in the FH gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Met164Cysfs2) in the FH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 2573279). For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Met164Cysfs*2) in the FH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 2573279). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.	Gardie B	Journal of medical genetics	2011	PMID: 21398687
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.	Tomlinson IP	Nature genetics	2002	PMID: 11865300

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000143.4(FH):c.490del (p.Met164fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...