Submissions for variant NM_006363.6(SEC23B):c.325G>A (p.Glu109Lys) (rs121918221)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000081407	SCV000113338	pathogenic	not provided	2013-11-18	criteria provided, single submitter	clinical testing
Invitae	RCV000688348	SCV000815954	pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2019-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 109 of the SEC23B protein (p.Glu109Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121918221, ExAC 0.06%). This is the most common variant associated with congenital dyserythropoietic anemia type II, which many homozygous affected individuals reported (PMID: 19561605, 19621418, 20015893, 21252497, 21850656, 25044164). ClinVar contains an entry for this variant (Variation ID: 1222). Experimental studies have shown that this missense change destabilizes the protein in cell culture (PMID: 19561605). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina	RCV000001281	SCV000915932	pathogenic	Congenital dyserythropoietic anemia, type II	2018-10-05	criteria provided, single submitter	clinical testing	The SEC23B c.325G>A (p.Glu109Lys) variant has been reported in at least three studies and is found in a total of 25 individuals including 23 in a homozygous state and two in a compound heterozygous state with congenital dyserythropoietic anemia (Schwarz et al. 2009; Bianchi et al. 2009; Punzo et al. 2011; Amir et al. 2011). The p.Glu109Lys variant is described as a founder mutation among the Israeli Moroccan Jewish population (Amir et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.000577 in the African population of the Exome Aggregation Consortium. Expression analysis in HeLa-Kyoto cells determined the p.Glu109Lys variant had less than 5% of wildtype expression (Schwarz et al. 2009). Based on the evidence, the p.Glu109Lys variant is classified as pathogenic for congenital dyserythropoietic anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000081407	SCV001249078	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001199102	SCV001370097	pathogenic	Hematological disease	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3,PP4,PP5. This variant was detected in homozygous state.
OMIM	RCV000001281	SCV000021431	pathogenic	Congenital dyserythropoietic anemia, type II	2009-09-01	no assertion criteria provided	literature only

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