Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000001283 | SCV004039080 | likely pathogenic | Congenital dyserythropoietic anemia, type II | 2023-08-11 | criteria provided, single submitter | clinical testing | Variant summary: SEC23B c.1588C>T (p.Arg530Trp) results in a non-conservative amino acid change located in the Sec23/Sec24, helical domain (IPR006900) of the encoded protein sequence. This alters a highly conserved residue in which another missense variant p.Arg530Gln) has been found in association with disease (HGMD). 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 1.6e-05 in 251468 control chromosomes (gnomAD). c.1588C>T has been reported in the literature in individuals affected with Congenital dyserythropoietic anemia, type II who were reported as compound heterozygous with other pathogenic variants (Schwarz_2009, Unal_2014). 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. The following publications have been ascertained in the context of this evaluation (PMID: 19561605, 24724984). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Mayo Clinic Laboratories, |
RCV003480015 | SCV004225467 | uncertain significance | not provided | 2022-08-09 | criteria provided, single submitter | clinical testing | PP3, PM2, PM3 |
| Invitae | RCV003764507 | SCV004568853 | pathogenic | Congenital dyserythropoietic anemia, type II; Cowden syndrome 7 | 2023-11-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 530 of the SEC23B protein (p.Arg530Trp). This variant is present in population databases (rs121918223, gnomAD 0.004%). This missense change has been observed in individuals with dyserythropoietic anemia type 2 (PMID: 19561605, 24724984). ClinVar contains an entry for this variant (Variation ID: 1224). 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 95%. Experimental studies have shown that this missense change affects SEC23B function (PMID: 19561605). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg530 amino acid residue in SEC23B. Other variant(s) that disrupt this residue have been observed in individuals with SEC23B-related conditions (PMID: 19561605, 20015893, 22208203, 24724984), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000001283 | SCV000021433 | pathogenic | Congenital dyserythropoietic anemia, type II | 2009-08-01 | no assertion criteria provided | literature only |