ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.983_986TCAC[1] (p.His330fs) (rs772359099)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000190585 SCV000245609 pathogenic Fanconi anemia, complementation group A 2014-10-07 criteria provided, single submitter clinical testing The p.His330AlafsX4 variant in FANCA has been reported in >10 homozygous or compound heterozygous individuals with Fanconi anemia (Levran 1997, Morgan 1999, Najim 2009, De Rocco 2014, FANCA LOVD database) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 330 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of FANCA function is an established disease mechanism in fanconia anemia. In summary, this variant meets our criteria to be classified as pathogenic for Fanconi anemia in an autosomal recessive manner (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/) due to the predicted impact to the protein.
GeneDx RCV000483448 SCV000567944 pathogenic not provided 2015-09-04 criteria provided, single submitter clinical testing The c.987_990delTCAC pathogenic variant in the FANCA gene has been reported previously in twoindividuals, one homozygous and one heterozygous, with Fanconi anemia (Levran et al., 1997). Thec.987_990delTCAC variant causes a frameshift starting with codon Histidine 330, changes this aminoacid to an Alanine residue, and creates a premature Stop codon at position 4 of the new reading frame,denoted p.His330AlafsX4. This variant is predicted to cause loss of normal protein function eitherthrough protein truncation or nonsense-mediated mRNA decay. The c.987_990delTCAC variant wasnot observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.We interpret c.987_990delTCAC as a pathogenic variant.
Counsyl RCV000190585 SCV000789247 pathogenic Fanconi anemia, complementation group A 2017-01-19 criteria provided, single submitter clinical testing
Invitae RCV000804476 SCV000944387 pathogenic Fanconi anemia 2018-08-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His330Alafs*4) in the FANCA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs772359099, ExAC 0.02%). This variant has been observed in many individuals affected with Fanconi anemia (PMID: 9371798, 28423363, 21273304, 17924555, 27041517), and in an individual affected with hereditary breast and ovarian cancer (PMID: 28423363). ClinVar contains an entry for this variant (Variation ID: 208580). Loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). For these reasons, this variant has been classified as Pathogenic.

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