Submissions for variant NM_006363.6(SEC23B):c.40C>T (p.Arg14Trp)

gnomAD frequency: 0.00017  dbSNP: rs121918222

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000153924	SCV000330039	pathogenic	not provided	2022-06-20	criteria provided, single submitter	clinical testing	One of the most common recurrent variants in the SEC23B gene and is considered a founder mutation in Italy, Morocco, and Israel (Russo et al., 2014); Published functional studies demonstrate a damaging effect: in vitro studies indicate the variant is unstable with less than 5% of the protein detectable compared to wild type (Schwarz et al., 2009); 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: 21850656, 23935019, 19621418, 29846281, 20015893, 22208203, 33159567, 19561605, 25044164, 34426522, 31589614, 32641076)
Eurofins Ntd Llc (ga)	RCV000153924	SCV000331589	pathogenic	not provided	2015-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV000688744	SCV000816367	pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2024-01-11	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 14 of the SEC23B protein (p.Arg14Trp). This variant is present in population databases (rs121918222, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia type II (PMID: 19561605, 19621418, 20015893, 21850656). 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: 1223). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SEC23B protein function. Experimental studies have shown that this missense change affects SEC23B function (PMID: 19561605). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000153924	SCV001249077	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	SEC23B: PS3:Very Strong, PS4, PP1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000153924	SCV001473847	pathogenic	not provided	2022-09-21	criteria provided, single submitter	clinical testing	The SEC23B c.40C>T; p.Arg14Trp variant (rs121918222) has been reported in the literature as a founder mutation associated with congenital dyserythropoietic anemia type II (CDA II) in the Italian population (Russo 2011). In CDA II patients, the p.Arg14Trp variant was always detected along with an additional SEC23B pathogenic variant as a compound heterozygote (Aydin Koker 2018, Bianchi 2009, Iolascon 2010, Mansour-Hendili 2020, Mendez 2021, Moreno-Carralero 2018, Punzo 2011, Schwarz 2009). This SEC23B variant is reported as pathogenic in ClinVar (Variation ID: 1223). This variant is found in the general population with an overall allele frequency of 0.02% (67/282848 alleles) in the Genome Aggregation Database. The arginine at codon 14 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.75). In addition, in vitro functional analyses demonstrate that Arg14Trp-mutated SEC23B is extremely unstable with less than 5% of residual protein activity (Schwarz 2009). Based on available information, this SEC23B variant is considered to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000153924	SCV001715310	pathogenic	not provided	2020-06-16	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM3, PP1, PP5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001282	SCV002767774	pathogenic	Congenital dyserythropoietic anemia, type II	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital dyserythropoietic anemia type II (MIM#224100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (67 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes) (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a compound heterozygous state with another pathogenic variant in multiple individuals (ClinVar, PMID: 19621418, 19561605, 25044164). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001494). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000688744	SCV002810960	pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2022-03-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000153924	SCV003825523	pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV000001282	SCV003853406	pathogenic	Congenital dyserythropoietic anemia, type II	2023-03-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000153924	SCV004027037	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
OMIM	RCV000001282	SCV000021432	pathogenic	Congenital dyserythropoietic anemia, type II	2009-09-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000153924	SCV001554357	pathogenic	not provided		no assertion criteria provided	clinical testing	The SEC23B p.R14W variant was identified in 36 of 178 proband chromosomes (frequency: 0.202; 1 homozygote, 3 heterozygotes, and 31 compound heterozygotes) from individuals or families with Congenital Dyserythropoietic Anemia type II (CDAII) (Punzo_2011_PMID:22208203; Russo_2011_PMID:21850656; Iolascon_2010_PMID:20015893; Bianchi_2009_PMID:19621418). A case report of an 18 year-old boy with chronic mild congenital anemia of unknown origin, chronic jaundice, and splenomegaly caused by non-autoimmune hemolytic anemia since 18 months of age was found to have two causative mutations in the SEC23B gene: the p.R14W variant and a novel frameshift deletion p.V164Wfs*3; the patient’s non-consanguineous parents with no history of anemia were heterozygous for either mutation (Koker_2018_PMID:29846281). The variant was identified in dbSNP (ID: rs121918222) and ClinVar (classified as pathogenic by Invitae, GeneDx and EGL Genetic Diagnostics for congenital dyserythropoietic anemia, type II). The variant was identified in control databases in 67 of 282848 chromosomes at a frequency of 0.0002369 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 21 of 35440 chromosomes (freq: 0.000593), Other in 4 of 7224 chromosomes (freq: 0.000554), European (non-Finnish) in 32 of 129154 chromosomes (freq: 0.000248), Ashkenazi Jewish in 2 of 10368 chromosomes (freq: 0.000193), East Asian in 3 of 19954 chromosomes (freq: 0.00015), South Asian in 3 of 30616 chromosomes (freq: 0.000098), African in 1 of 24972 chromosomes (freq: 0.00004), and European (Finnish) in 1 of 25120 chromosomes (freq: 0.00004). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg14 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies demonstrated that the p.R14W variant resulted in <5% of detectable protein compared to wildtype, however the p.R14W variant was coimmunoprecipitated by SEC24D simlarly to wildtype (Schwarz_2009_PMID:19561605). In addition, Satchwell et al. conducted in vitro studies to track the appearance of the CDAII phenotype during erythroblast differentiation in 5 unrelated patients, 3 of whom were compound heterozygotes for the p.R14W variant; patient erythroblasts displayed the characteristic CDAII phenotype including multinuclearity, erythrocyte membrane protein hypoglycosylation, and residual endoplasmic reticulum (Satchwell_2013_PMID:23935019). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.