Submissions for variant NM_004629.2(FANCG):c.1480+1G>C

gnomAD frequency: 0.00002  dbSNP: rs149616199

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630837	SCV000751806	pathogenic	Fanconi anemia	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 of the FANCG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCG are known to be pathogenic (PMID: 12552564). This variant is present in population databases (rs149616199, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with Fanconi anemia, complementation group G (PMID: 9806548, 12552564). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS11+1G>C. ClinVar contains an entry for this variant (Variation ID: 6717). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000007109	SCV000894466	pathogenic	Fanconi anemia complementation group G	2021-07-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001564939	SCV001788185	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9806548, 22778927, 12031647, 21659346, 25236480, 28717661, 12552564, 11438206, 29625052, 26689913)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000630837	SCV003844656	pathogenic	Fanconi anemia	2023-02-02	criteria provided, single submitter	clinical testing	Variant summary: FANCG c.1480+1G>C 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: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251494 control chromosomes. c.1480+1G>C has been reported in the literature as a homozygous and compound heterozygous genotype in multiple individuals affected with Fanconi Anemia (Example: Tsangaris_2011, Lauhasurayotin_2019, Auerbach_2003, deWinter_1998) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000007109	SCV004199155	pathogenic	Fanconi anemia complementation group G	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000007109	SCV000027305	pathogenic	Fanconi anemia complementation group G	2003-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000007109	SCV000058054	not provided	Fanconi anemia complementation group G		no assertion provided	literature only	Common in French Canadians & northern Europeans
Leiden Open Variation Database	RCV000007109	SCV001364837	pathogenic	Fanconi anemia complementation group G	2011-02-07	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV000007109	SCV001452298	pathogenic	Fanconi anemia complementation group G	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748504	SCV005360063	pathogenic	FANCG-related disorder	2024-08-16	no assertion criteria provided	clinical testing	The FANCG c.1480+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also known as IVS11+1G>C, has been reported in several patients with Fanconi anemia and is a founder variant in the French Canadian population (de Winter et al. 1998. PubMed ID: 9806548; Auerbach et al. 2003. PubMed ID: 12552564; Gille et al. 2012. PubMed ID: 22778927; http://www.rockefeller.edu/fanconi/). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in FANCG are expected to be pathogenic. This variant is interpreted as pathogenic.