VCV002675670.2 - ClinVar

NM_018062.4(FANCL):c.1039_1042dup (p.Ser348delinsAsnTer)

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.

(2)

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_018062.4(FANCL):c.1039_1042dup (p.Ser348delinsAsnTer)

Variation ID: 2675670 Accession: VCV002675670.2

Type and length

Microsatellite, 4 bp

Location

Cytogenetic: 2p16.1 2: 58160157-58160158 (GRCh38) [ NCBI UCSC ] 2: 58387292-58387293 (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	Dec 30, 2023	Feb 14, 2024	Sep 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_018062.4:c.1039_1042dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060532.2:p.Ser348delinsAsnTer	nonsense
NM_001114636.2:c.1047_1050ACTA[3]	NP_001108108.1:p.Leu351Thrfs	frameshift
NM_001374615.1:c.1084_1087dup	NP_001361544.1:p.Ser363delinsAsnTer	nonsense
NM_001410792.1:c.1099_1102dup	NP_001397721.1:p.Ser368delinsAsnTer	nonsense
NR_156742.2:n.766_769ACTA[3]
NR_164659.2:n.931_934ACTA[3]
NC_000002.12:g.58160158TAGT[3]
NC_000002.11:g.58387293TAGT[3]
NG_007418.1:g.86215ACTA[3]
NG_029717.2:g.257418TAGT[3]
LRG_501:g.86215ACTA[3]
LRG_501t1:c.1054_1057dup	LRG_501p1:p.Ser353delinsAsnTer
LRG_501t2:c.1032_1035ACTA[3]	LRG_501p2:p.Leu346Thrfs

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:58160157:TAGTTAGT:TAGTTAGTTAGT

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.
FANCL		-	-	GRCh38 GRCh37	688	761

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.
Fanconi anemia complementation group L	Likely pathogenic (1)	criteria provided, single submitter	Feb 1, 2023	RCV003468186.1
Fanconi anemia	Likely pathogenic (1)	criteria provided, single submitter	Sep 28, 2023	RCV003523190.2

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 (Feb 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group L Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004197276.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (Sep 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi anemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004300757.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 12973351‚ 17938197‚ 19111657‚ 24389026‚ 26149689 Comment: 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 … (more) 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. This variant disrupts the PHD/RING finger domain of the FANCL protein, which is necessary for FANCL interaction with Ube2t and Ube2w, and subsequent monoubiquitination of FANCD2 (PMID: 12973351, 17938197, 19111657, 24389026, 26149689). While functional studies have not been performed to directly test the effect of this variant on FANCL protein function, this suggests that disruption of this region of the protein is causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with FANCL-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ser348Asnfs*2) in the FANCL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the FANCL protein. (less)

Comment:

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. This variant disrupts the PHD/RING finger domain of the FANCL protein, which is necessary for FANCL interaction with Ube2t and Ube2w, and subsequent monoubiquitination of FANCD2 (PMID: 12973351, 17938197, 19111657, 24389026, 26149689). While functional studies have not been performed to directly test the effect of this variant on FANCL protein function, this suggests that disruption of this region of the protein is causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with FANCL-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ser348Asnfs*2) in the FANCL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the FANCL protein.

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
The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.	Miles JA	The Journal of biological chemistry	2015	PMID: 26149689
Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection.	Hodson C	Structure (London, England : 1993)	2014	PMID: 24389026
Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI.	Alpi AF	Molecular cell	2008	PMID: 19111657
UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination.	Alpi A	Molecular and cellular biology	2007	PMID: 17938197
A novel ubiquitin ligase is deficient in Fanconi anemia.	Meetei AR	Nature genetics	2003	PMID: 12973351

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_018062.4(FANCL):c.1039_1042dup (p.Ser348delinsAsnTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...