Submissions for variant NM_006363.6(SEC23B):c.835-2A>G

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003787891	SCV004604725	pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2024-11-16	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the SEC23B 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 SEC23B are known to be pathogenic (PMID: 19561605, 25044164). This variant is present in population databases (rs371646735, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with congenital dyserythropoietic anemia type II (PMID: 27471141, 29901818). ClinVar contains an entry for this variant (Variation ID: 2922725). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240919	SCV005887999	likely pathogenic	Congenital dyserythropoietic anemia, type II	2025-01-07	criteria provided, single submitter	clinical testing	Variant summary: SEC23B c.835-2A>G 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of SEC23B function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251454 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SEC23B causing Congenital dyserythropoietic anemia, type II, allowing no conclusion about variant significance. c.835-2A>G has been reported in the literature in the heterozygous and compound heterozygous state in individuals affected with Congenital dyserythropoietic anemia, type II (Bianchi_2016, Musri_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital dyserythropoietic anemia, type II. 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: 27471141, 37373084). ClinVar contains an entry for this variant (Variation ID: 2922725). Based on the evidence outlined above, the variant was classified as likely pathogenic.