Submissions for variant NM_006363.6(SEC23B):c.2101C>T (p.Arg701Cys)

gnomAD frequency: 0.00005  dbSNP: rs201270568

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002020875	SCV002306888	pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2024-02-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 701 of the SEC23B protein (p.Arg701Cys). This variant is present in population databases (rs201270568, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Cowden syndrome and/or dyserythropoietic anemia type 2 (PMID: 19621418, 20015893, 20381388, 26522472). ClinVar contains an entry for this variant (Variation ID: 1515145). 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 SEC23B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222748	SCV002500273	likely pathogenic	SEC23B-related disorder	2022-03-09	criteria provided, single submitter	clinical testing	Variant summary: SEC23B c.2101C>T (p.Arg701Cys) results in a non-conservative amino acid change located in the Gelsolin-like domain (IPR007123) of the encoded protein sequence. Arg701 is thought to form critical catalytic interactions with GTP and the other COPII component Sar1 (Fermo_2010) and the introduction of a new Cys residue may modify the domain orientation through the formation of new disulfide bonds. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251472 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SEC23B causing SEC23B-Related Disorders, allowing no conclusion about variant significance. c.2101C>T has been reported in the literature as a compound heterozygous genotype in individuals with Congenital Dyserythropoietic Anemia Type II (CDAII) (example, Bianchi_2009, Iolascon_2010, Fermo_2010) and continues to be cited by others (example, Punzo_2011, Zhang_2019). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV003130680	SCV003812717	likely pathogenic	not provided	2022-12-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003130680	SCV005050730	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SEC23B: PM2, PM5, PS4:Moderate, PP3
Fulgent Genetics, Fulgent Genetics	RCV002020875	SCV005656389	likely pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2024-05-17	criteria provided, single submitter	clinical testing