20-18510875-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_006363.6(SEC23B):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_006363.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000178 AC: 27AN: 152088Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000235 AC: 59AN: 251450Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135900
GnomAD4 exome AF: 0.000118 AC: 173AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90AN XY: 727242
GnomAD4 genome AF: 0.000178 AC: 27AN: 152088Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74274
ClinVar
Submissions by phenotype
not provided Pathogenic:8
SEC23B: PM3:Very Strong, PM2, PP3, PS3:Supporting -
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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. -
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 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 (v2.1.1). 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 variant is considered to be pathogenic. References: Aydin Koker S et al. Identification of a Novel Mutation in the SEC23B Gene Associated With Congenital Dyserythropoietic Anemia Type II Through the Use of Next-generation Sequencing Panel in an Undiagnosed Case of Nonimmune Hereditary Hemolytic Anemia. J Pediatr Hematol Oncol. 2018 Oct. PMID: 29846281. Bianchi P et al. Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene. Hum Mutat. 2009 Sep. PMID: 19621418. Iolascon A et al. Molecular analysis of 42 patients with congenital dyserythropoietic anemia type II: new mutations in the SEC23B gene and a search for a genotype-phenotype relationship. Haematologica. 2010 May. PMID: 20015893. Mansour-Hendili L et al. Exome sequencing for diagnosis of congenital hemolytic anemia. Orphanet J Rare Dis. 2020 Jul 8. PMID: 32641076. Mendez M et al. Congenital dyserythropoietic anemia types Ib, II, and III: novel variants in the CDIN1 gene and functional study of a novel variant in the KIF23 gene. Ann Hematol. 2021 Feb. PMID: 33159567. Moreno-Carralero MI et al. Clinical and genetic features of congenital dyserythropoietic anemia (CDA). Eur J Haematol. 2018 Sep. PMID: 29901818. Punzo F et al. Congenital dyserythropoietic anemia type II: molecular analysis and expression of the SEC23B gene. Orphanet J Rare Dis. 2011 Dec 30. PMID: 2220820. Russo R et al. Two founder mutations in the SEC23B gene account for the relatively high frequency of CDA II in the Italian population. Am J Hematol. 2011 Sep. PMID: 21850656. Schwarz K et al. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nature genetics. 2009 Aug. PMID: 19561605. -
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) -
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Congenital dyserythropoietic anemia, type II Pathogenic:4
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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 -
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Congenital dyserythropoietic anemia, type II;C4225179:Cowden syndrome 7 Pathogenic:2
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. -
SEC23B-related disorder Pathogenic:1
The SEC23B c.40C>T variant is predicted to result in the amino acid substitution p.Arg14Trp. This variant has been reported to be causative for autosomal recessive congenital dyserythropoietic anemia (CDA) type II in the homozygous or compound heterozygous states (Bianchi et al. 2009. PubMed ID: 19621418; Schwarz et al. 2009. PubMed ID: 19561605; Iolascon et al. 2010. PubMed ID: 20015893; Russo et al. 2011. PubMed ID: 21850656). This variant is reported in 0.059% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at