VCV001757309.6 - ClinVar

NM_000143.4(FH):c.712G>C (p.Asp238His)

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.

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.712G>C (p.Asp238His)

Variation ID: 1757309 Accession: VCV001757309.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q43 1: 241508629 (GRCh38) [ NCBI UCSC ] 1: 241671929 (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	Nov 29, 2022	May 1, 2024	Nov 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000143.4:c.712G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000134.2:p.Asp238His	missense
NC_000001.11:g.241508629C>G
NC_000001.10:g.241671929C>G
NG_012338.1:g.16126G>C
LRG_504:g.16126G>C
LRG_504t1:c.712G>C	LRG_504p1:p.Asp238His

... more HGVS ... less HGVS

Protein change

D238H

Other names

Canonical SPDI

NC_000001.11:241508628:C:G

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	2034	2120

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 cancer-predisposing syndrome	no classifications from unflagged records (1)	no classifications from unflagged records	May 31, 2024	RCV002367462.4
not provided	Likely pathogenic (1)	criteria provided, single submitter	Nov 17, 2023	RCV003098478.4
Hereditary leiomyomatosis and renal cell cancer	Likely pathogenic (1)	criteria provided, single submitter	Jan 31, 2023	RCV003138224.2

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.
Likely pathogenic (Jan 31, 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: SCV003806655.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Publications: PubMed (2) PubMed: 35216667‚ 35874919 Comment: This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35216667, 35874919, Myriad internal … (more) This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35216667, 35874919, Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 35216667]. This variant is expected to disrupt protein structure [internal Myriad data]. (less)
Likely pathogenic (Nov 17, 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: SCV003328621.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 35216667 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 238 of the FH protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 238 of the FH protein (p.Asp238His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 1757309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 35216667). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Nov 25, 2021)	Flagged submission flagged submission (Ambry Variant Classification Scheme 2023) Method: clinical testing Reason: Older and outlier claim with insufficient supporting evidence Source: ClinGen	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002665779.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.D238H variant (also known as c.712G>C), located in coding exon 5 of the FH gene, results from a G to C substitution at nucleotide … (more) The p.D238H variant (also known as c.712G>C), located in coding exon 5 of the FH gene, results from a G to C substitution at nucleotide position 712. The aspartic acid at codon 238 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35216667, 35874919, Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 35216667]. This variant is expected to disrupt protein structure [internal Myriad data].

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 238 of the FH protein (p.Asp238His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 1757309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 35216667). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The p.D238H variant (also known as c.712G>C), located in coding exon 5 of the FH gene, results from a G to C substitution at nucleotide position 712. The aspartic acid at codon 238 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers.	Jikuya R	iScience	2022	PMID: 35874919
Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.	Ge X	Molecular cell	2022	PMID: 35216667

Text-mined citations for this variant ...

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000143.4(FH):c.712G>C (p.Asp238His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...