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NM_000135.4(FANCA):c.987_990del (p.His330fs) AND Fanconi anemia complementation group A

Germline classification:
Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:
Oct 21, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000190585.12

Allele description [Variation Report for NM_000135.4(FANCA):c.987_990del (p.His330fs)]

NM_000135.4(FANCA):c.987_990del (p.His330fs)

Gene:
FANCA:FA complementation group A [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
16q24.3
Genomic location:
Preferred name:
NM_000135.4(FANCA):c.987_990del (p.His330fs)
HGVS:
  • NC_000016.10:g.89795924GAGT[1]
  • NG_011706.1:g.25729TCAC[1]
  • NM_000135.4:c.987_990delMANE SELECT
  • NM_001286167.3:c.987_990del
  • NP_000126.2:p.His330fs
  • NP_001273096.1:p.His330fs
  • LRG_495t1:c.987_990del
  • LRG_495:g.25729TCAC[1]
  • NC_000016.9:g.89862332GAGT[1]
  • NM_000135.2:c.987_990del
  • NM_000135.2:c.987_990delTCAC
  • NM_000135.3:c.987_990del
Protein change:
H330fs
Links:
dbSNP: rs772359099
NCBI 1000 Genomes Browser:
rs772359099
Molecular consequence:
  • NM_000135.4:c.987_990del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001286167.3:c.987_990del - frameshift variant - [Sequence Ontology: SO:0001589]
Observations:
1

Condition(s)

Name:
Fanconi anemia complementation group A
Synonyms:
Fanconi anemia, group A
Identifiers:
MONDO: MONDO:0009215; MedGen: C3469521; Orphanet: 84; OMIM: 227650

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000245609Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq
criteria provided, single submitter

(LMM Criteria)
Pathogenic
(Oct 7, 2014)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000789247Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Pathogenic
(Jan 19, 2017)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001426042Leiden Open Variation Database
no assertion criteria provided
Pathogenic
(Feb 28, 2020)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

SCV002798338Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 17, 2022)
unknownclinical testing

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

SCV0038415903billion
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 23, 2023)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004195996Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Oct 21, 2023)
unknownclinical testing

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

SCV004238184Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 3, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedcuration
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations.

Castella M, Pujol R, Callén E, Trujillo JP, Casado JA, Gille H, Lach FP, Auerbach AD, Schindler D, Benítez J, Porto B, Ferro T, Muñoz A, Sevilla J, Madero L, Cela E, Beléndez C, de Heredia CD, Olivé T, de Toledo JS, Badell I, Torrent M, et al.

Blood. 2011 Apr 7;117(14):3759-69. doi: 10.1182/blood-2010-08-299917. Epub 2011 Jan 27.

PubMed [citation]
PMID:
21273304
PMCID:
PMC3083295
See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq, SCV000245609.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Counsyl, SCV000789247.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Leiden Open Variation Database, SCV001426042.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter.

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

From Fulgent Genetics, Fulgent Genetics, SCV002798338.1

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

From 3billion, SCV003841590.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000208580 / PMID: 9371798). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Baylor Genetics, SCV004195996.1

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

From Revvity Omics, Revvity, SCV004238184.1

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

Last Updated: Sep 29, 2024