Submissions for variant NM_000135.4(FANCA):c.3971C>T (p.Pro1324Leu)

gnomAD frequency: 0.00001  dbSNP: rs182657062

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494388	SCV000582809	pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, showing that P1324L resulted in mild impairment of FANCA function (Adachi et al., 2002).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17924555, 25525159, 31589614, 33270637, 23973728, 10521298, 32054657, 24584348, 12444097)
Counsyl	RCV000666624	SCV000790945	likely pathogenic	Fanconi anemia complementation group A	2017-04-17	criteria provided, single submitter	clinical testing
Invitae	RCV001219227	SCV001391153	pathogenic	Fanconi anemia	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1324 of the FANCA protein (p.Pro1324Leu). This variant is present in population databases (rs182657062, gnomAD 0.01%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 10521298, 17924555, 23973728, 24584348). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 430085). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FANCA protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000666624	SCV002024577	likely pathogenic	Fanconi anemia complementation group A	2019-12-27	criteria provided, single submitter	clinical testing
3billion	RCV000666624	SCV002521680	pathogenic	Fanconi anemia complementation group A	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12444097). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.29). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430085). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10521298, 17924555, 23973728). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000666624	SCV004196086	pathogenic	Fanconi anemia complementation group A	2023-07-04	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000666624	SCV001426129	pathogenic	Fanconi anemia complementation group A	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.