Submissions for variant NM_000246.4(CIITA):c.2651G>A (p.Arg884His)

gnomAD frequency: 0.00048  dbSNP: rs374443915

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000352360	SCV000394766	uncertain significance	MHC class II deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000352360	SCV000898613	uncertain significance	MHC class II deficiency	2017-11-21	criteria provided, single submitter	clinical testing	CIITA NM_000246.3 exon 11 p.Arg884His (c.2651G>A): This variant has not been reported in the literature but is present in 0.1% (21/16688) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs374443915). This variant is present in ClinVar (Variation ID:317716). This variant amino acid Histidine (His) is present in >20 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Fulgent Genetics, Fulgent Genetics	RCV002487397	SCV002780155	uncertain significance	MHC class II deficiency; Rheumatoid arthritis	2021-07-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000352360	SCV003247207	uncertain significance	MHC class II deficiency	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 884 of the CIITA protein (p.Arg884His). This variant is present in population databases (rs374443915, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CIITA-related conditions. ClinVar contains an entry for this variant (Variation ID: 317716). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002487397	SCV003919805	uncertain significance	MHC class II deficiency; Rheumatoid arthritis	2021-03-30	criteria provided, single submitter	clinical testing	CIITA NM_000246 exon 11 p.Arg884His (c.2651G>A): This variant has not been reported in the literature but is present in 0.1% (21/16688) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs374443915). This variant is present in ClinVar (Variation ID:317716). This variant amino acid Histidine (His) is present in >20 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV004021643	SCV004927394	likely benign	Inborn genetic diseases	2023-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV000352360	SCV001464786	likely benign	MHC class II deficiency	2020-04-24	no assertion criteria provided	clinical testing