Submissions for variant NM_000135.4(FANCA):c.2778+1G>A

gnomAD frequency: 0.00002  dbSNP: rs140180549

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811488	SCV000951756	pathogenic	Fanconi anemia	2023-09-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 28, but is expected to preserve the integrity of the reading-frame (PMID: 24584348). ClinVar contains an entry for this variant (Variation ID: 635518). Disruption of this splice site has been observed in individuals with Fanconi anemia (PMID: 23067021, 24584348, 29098742). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change affects a donor splice site in intron 28 of the FANCA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
GeneDx	RCV002269312	SCV002552606	pathogenic	not provided	2022-07-24	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29753700, 29098742, 24584348)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000786986	SCV002768139	pathogenic	Fanconi anemia complementation group A	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anemia of complementation group A (MIM#227650). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 3 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2) at a frequency of 0.00000398 (c.2778+1G>T: 1 heterozygote, 0 homozygotes). (SB) 0508 - In silico predictions for abnormal splicing are inconclusive. While NetGene2 predicted a loss of the WT donor site, Fruitfly did not predict the presence of a WT donor site. It should also be noted that the affected nucleotide is highly conserved. (I) 0702 - Other canonical splice variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The c.2778+1G>C variant was identified in one individual with Fanconi anemia-associated bone marrow failure and classified as pathogenic by one clinical diagnostic laboratory, while c.2778+1G>T was reported in one individual with Fanconi anemia (PMIDs: 23067021, 28717661, ClinVar). Additionally, c.2778+2T>C was identified in one individual with Fanconi anemia and has been classified as likely pathogenic and pathogenic by two clinical diagnostic laboratories (PMID: 31558676, ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as compound heterozygous in two individuals with Fanconi anemia and has been classified as pathogenic by clinical diagnostic laboratories (PMIDs: 24584348, 29098742, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV002269312	SCV004010536	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	FANCA: PVS1, PM2, PS3:Moderate
Baylor Genetics	RCV000786986	SCV004196066	pathogenic	Fanconi anemia complementation group A	2024-03-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000811488	SCV005205420	pathogenic	Fanconi anemia	2024-06-03	criteria provided, single submitter	clinical testing	Variant summary: FANCA c.2778+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251436 control chromosomes (gnomAD). c.2778+1G>A has been reported in the literature in individuals affected with Fanconi Anemia (De Rocco_2014, Chang_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36463940, 24584348, 29753700). ClinVar contains an entry for this variant (Variation ID: 635518). Based on the evidence outlined above, the variant was classified as pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786986	SCV000925892	pathogenic	Fanconi anemia complementation group A	2018-11-23	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000786986	SCV001426095	uncertain significance	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV000811488	SCV002092582	pathogenic	Fanconi anemia	2021-06-02	no assertion criteria provided	clinical testing