NM_000136.3(FANCC):c.1661T>C (p.Leu554Pro) AND Fanconi anemia, complementation group C

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 14, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
7 submissions [Details]
Record status:
current
Accession:
RCV000012823.11

Allele description [Variation Report for NM_000136.3(FANCC):c.1661T>C (p.Leu554Pro)]

NM_000136.3(FANCC):c.1661T>C (p.Leu554Pro)

Genes:
FANCC:FA complementation group C [Gene - OMIM - HGNC]
AOPEP:aminopeptidase O (putative) [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q22.32
Genomic location:
Preferred name:
NM_000136.3(FANCC):c.1661T>C (p.Leu554Pro)
HGVS:
  • NC_000009.12:g.95101723A>G
  • NG_011707.1:g.220987T>C
  • NM_000136.3:c.1661T>CMANE SELECT
  • NM_001243743.2:c.1661T>C
  • NP_000127.2:p.Leu554Pro
  • NP_000127.2:p.Leu554Pro
  • NP_001230672.1:p.Leu554Pro
  • LRG_497t1:c.1661T>C
  • LRG_497:g.220987T>C
  • LRG_497p1:p.Leu554Pro
  • NC_000009.11:g.97864005A>G
  • NM_000136.2:c.1661T>C
  • Q00597:p.Leu554Pro
Protein change:
L554P; LEU554PRO
Links:
UniProtKB: Q00597#VAR_005233; OMIM: 613899.0001; dbSNP: rs104886458
NCBI 1000 Genomes Browser:
rs104886458
Molecular consequence:
  • NM_000136.3:c.1661T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243743.2:c.1661T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Fanconi anemia, complementation group C (FANCC)
Synonyms:
FANCONI PANCYTOPENIA, TYPE 3; FACC; Fanconi anemia, group C
Identifiers:
MONDO: MONDO:0009213; MedGen: C3468041; Orphanet: 84; OMIM: 227645

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000033063OMIMno assertion criteria providedPathogenic
(Feb 1, 1993)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

Gavish, H., dos Santos, C. C., Buchwald, M. Generation of a non-functional Fanconi anemia group C protein (FACC) by site-directed in vitro mutagenesis. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A128-only, 1992.,

SCV000057806GeneReviewsno assertion criteria providedPathogenic
(Jun 1, 2021)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV001132190Counsylno assertion criteria providedLikely pathogenic
(Oct 9, 2018)
unknownclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001163619Baylor Geneticscriteria provided, single submitter
Likely pathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001363461Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Oct 14, 2019)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV001365344Leiden Open Variation Databaseno assertion criteria providedPathogenic
(Feb 28, 2020)
germlinecuration

PubMed (1)
[See all records that cite this PMID]

SCV002022325PerkinElmer Genomicsno assertion criteria providedPathogenic
(Apr 23, 2019)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedliterature only, clinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Cytoplasmic localization of FAC is essential for the correction of a prerepair defect in Fanconi anemia group C cells.

Youssoufian H.

J Clin Invest. 1996 May 1;97(9):2003-10.

PubMed [citation]
PMID:
8621788
PMCID:
PMC507273

Fanconi Anemia.

Mehta PA, Ebens C.

2002 Feb 14 [updated 2021 Jun 3]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.

PubMed [citation]
PMID:
20301575
See all PubMed Citations (16)

Details of each submission

From OMIM, SCV000033063.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

Strathdee et al. (1992) and Gavish et al. (1992) demonstrated that HSC536N cells, which represented the only confirmed Fanconi anemia cell line of complementation group C (FANCC; 227645), have a T-to-C transition at base 1913 that changes codon 553 from leucine to proline (L553P). Gavish et al. (1993) corrected the previously published FACC cDNA sequence which omitted 3 nucleotides. The corrected sequence predicts a 1,677-bp ORF and a protein of 558 amino acids. Therefore, the previously reported L553P mutation is, in fact, L554P. To avoid confusion, they chose to refer to the site of the mutation as base 1661, on the basis of the ORF, and amino acid 554 on the basis of its location in the protein. Using site-directed in vitro mutagenesis, Gavish et al. (1993) demonstrated that the leu554-to-pro mutation completely abolishes the activity of the FACC protein as analyzed by functional complementation assay.

The polypeptide encoded by the FAC gene binds to a group of cytoplasmic proteins in vitro and may form a multimeric complex. The leu554-to-pro mutant allele fails to correct the sensitivity of FA group C cells to mitomycin C. Youssoufian et al. (1996) reasoned that overexpression of the mutant protein in a wildtype cellular background might induce the FA phenotype by competing with endogenous FAC for binding to the accessory proteins. After stable transfection of human kidney 293 cells with wildtype and a mutant FAC allele containing the L554P substitution, 4 independent clones that expressed 4- to 15-fold higher levels of transcript from the mutant transgene relative to the endogenous FAC gene showed hypersensitivity to mitomycin C. By contrast, both parental and FAC-overexpressing cells maintained their relative resistance to mitomycin C. No differences in the biosynthesis, subcellular localization, and protein interactions of the normal and mutant proteins were detected. Youssoufian et al. (1996) stated that the induction of the FA phenotype in this system is compatible with the competition hypothesis and provides support for a functional role of the FAC-binding proteins in vivo.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000057806.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV001132190.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001163619.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363461.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

Variant summary: FANCC c.1661T>C (p.Leu554Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251192 control chromosomes (gnomAD). c.1661T>C has been reported in the literature in individuals affected with Fanconi Anemia (e.g. Strathdee_1992, Dokal_1996, Gillio_1997). These data indicate that the variant may be associated with disease. The variant has also been detected in at least one individual with bilateral breast cancer and a family history of the diseae (Thompson_2012). Several publications report experimental evidence evaluating an impact on protein function, reporting significantly reduced capacity for DNA repair and disruption of the protein's ability to bind FAA ( (e.g. Gavish_1993, Kupfer_1997, Donahue_2004). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Leiden Open Variation Database, SCV001365344.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From PerkinElmer Genomics, SCV002022325.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

Support Center