ClinVar Genomic variation as it relates to human health
NM_018062.4(FANCL):c.1092G>A (p.Lys364=)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018062.4(FANCL):c.1092G>A (p.Lys364=)
Variation ID: 929823 Accession: VCV000929823.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.1 2: 58160108 (GRCh38) [ NCBI UCSC ] 2: 58387243 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 28, 2020 Feb 20, 2024 Nov 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018062.4:c.1092G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060532.2:p.Lys364= synonymous NM_001114636.2:c.1107G>A NP_001108108.1:p.Lys369= synonymous NM_001374615.1:c.1137G>A NP_001361544.1:p.Lys379= synonymous NM_001410792.1:c.1152G>A NP_001397721.1:p.Lys384= synonymous NR_156742.2:n.826G>A NR_164659.2:n.991G>A NC_000002.12:g.58160108C>T NC_000002.11:g.58387243C>T NG_007418.1:g.86272G>A NG_029717.2:g.257368C>T LRG_501:g.86272G>A LRG_501t1:c.1107G>A LRG_501p1:p.Lys369= LRG_501t2:c.1092G>A LRG_501p2:p.Lys364= - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:58160107:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00000 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
- Links
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 | ||
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HI score
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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. |
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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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2023 | RCV001195068.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 2, 2023 | RCV001381353.5 |
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. |
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Pathogenic
(Jun 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004021151.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: FANCL c.1092G>A (p.Lys364Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a … (more)
Variant summary: FANCL c.1092G>A (p.Lys364Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens the canonical 5' donor site. Experimental evidence supports this variant alters mRNA splicing and likely results in a shortened protein product (examples: Chandrasekharappa_2013 and Donovan_2020). The variant allele was found at a frequency of 2e-05 in 250742 control chromosomes (gnomAD). c.1092G>A has been reported in the literature in multiple bi-allelic individuals affected with Fanconi Anemia (examples: Chandrasekharappa_2013 and Donovan_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. One study demonstrated monoubiquitinated long-form of FANCD2 protein was undetectable in cells derived from an individual homozygous for this variant and had increased levels of G2/M phase accumulation, confirming that the variant results in a FA cellular phenotype (Donovan_2020). The following publications have been ascertained in the context of this evaluation (PMID: 23613520, 31513304). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group L
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100909.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The synonymous variant p.K364= in FANCL (NM_018062.3) has been reported previously in homozygous or compound heterozygous states in patients with Fanconi anemia. It is a … (more)
The synonymous variant p.K364= in FANCL (NM_018062.3) has been reported previously in homozygous or compound heterozygous states in patients with Fanconi anemia. It is a Founder variant in the South Asian population and is responsible for high number of fanconi anemia cases in India (Donovan FX et al). The variant has been submitted to ClinVar as Pathogenic. Functional studies demonstrate aberrant splicing. The p.K364= variant is observed in 5/30,596 (0.0163%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The nucleotide c.1092 in FANCL is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group L
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004197258.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group L
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023040.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001579711.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 364 of the FANCL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 364 of the FANCL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FANCL protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs577063114, gnomAD 0.02%). This variant has been observed in individuals with Fanconi anemia (PMID: 23613520, 31513304). ClinVar contains an entry for this variant (Variation ID: 929823). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 13, but is expected to preserve the integrity of the reading-frame (PMID: 23613520, 31513304). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 05, 2014)
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no assertion criteria provided
Method: curation
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Fanconi anemia complementation group L
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001365353.1
First in ClinVar: Jun 28, 2020 Last updated: Jun 28, 2020 |
Comment:
Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India. | Donovan FX | Human mutation | 2020 | PMID: 31513304 |
Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. | Chandrasekharappa SC | Blood | 2013 | PMID: 23613520 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs577063114 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.