Submissions for variant NM_000410.4(HFE):c.1006+1G>A

gnomAD frequency: 0.00004  dbSNP: rs573745685

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
School of Computer Science, University of Waterloo	RCV001376186	SCV001573238	likely pathogenic	Hemochromatosis type 1	2021-05-06	criteria provided, single submitter	clinical testing	Evidence categories PVS1 and PM2 in ACMG guidelines. This is a splice donor variant in gene HFE that may disrupt mRNA splicing and result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001376186	SCV002103476	likely pathogenic	Hemochromatosis type 1	2022-02-17	criteria provided, single submitter	clinical testing	Variant summary: HFE c.1006+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 allele was found at a frequency of 6.4e-05 in 251332 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HFE causing Hemochromatosis Type 1 (6.4e-05 vs 0.046), allowing no conclusion about variant significance. c.1006+1G>A has been reported in the literature in individuals affected with Hemochromatosis Type 1 (Hamdi-Roze_2016). However, a case-control study showed that this variant was not associated with serum ferritin or transferrin saturation (Steiner_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS.
Fulgent Genetics, Fulgent Genetics	RCV002493912	SCV002798294	pathogenic	Variegate porphyria; Microvascular complications of diabetes, susceptibility to, 7; Alzheimer disease type 1; Hemochromatosis type 1; TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2; Familial porphyria cutanea tarda	2022-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002550228	SCV003523426	pathogenic	Hereditary hemochromatosis	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the HFE gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs573745685, gnomAD 0.08%). Disruption of this splice site has been observed in individuals with hereditary hemochromatosis (PMID: 11875012, 17240320, 27518069). ClinVar contains an entry for this variant (Variation ID: 1065637). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 11875012). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001376186	SCV003802012	likely pathogenic	Hemochromatosis type 1	2023-02-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001376186	SCV003834236	likely pathogenic	Hemochromatosis type 1	2022-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV003145645	SCV004023621	likely pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing; RNA analysis has demonstrated skipping of exon 5 (Steiner et al., 2002); Common variant among the Kinh Vietnamese (KHV) people (Le et al., 2019); This variant is associated with the following publications: (PMID: 25525159, 20008199, 17661915, 15965644, 31180159, 16570681, 12737949, 17240320, 26456104, 23577916, 16234038, 16132052, 11875012, 15182337, 16443912, 27518069)
Neuberg Centre For Genomic Medicine, NCGM	RCV001376186	SCV005042807	likely pathogenic	Hemochromatosis type 1		criteria provided, single submitter	clinical testing
GeneReviews	RCV001376186	SCV004100678	not provided	Hemochromatosis type 1		no assertion provided	literature only