Submissions for variant NM_000246.4(CIITA):c.413T>C (p.Val138Ala)

gnomAD frequency: 0.00072  dbSNP: rs142469968

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690043	SCV000817720	uncertain significance	MHC class II deficiency	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 138 of the CIITA protein (p.Val138Ala). This variant is present in population databases (rs142469968, gnomAD 0.2%). 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: 569422). 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 alanine 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	RCV001281060	SCV001468485	uncertain significance	MHC class II deficiency; Rheumatoid arthritis	2021-03-30	criteria provided, single submitter	clinical testing	CIITA NM_00246.3 exon 5 p.Val138Ala (c.413T>C): This variant has not been reported in the literature but is present in 0.1% (46/24946) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-10992836-T-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:569422). This variant amino acid Alanine (Ala) is present in >30 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.
New York Genome Center	RCV000690043	SCV001761072	uncertain significance	MHC class II deficiency	2020-07-03	criteria provided, single submitter	clinical testing	The homozygous c.413T>C (p.Val138Ala) variant identified in the CIITA gene substitutes a moderately conserved Valine for Alanine at amino acid 138/1131 (exon 5/20). The Valine at this position is replaced by an Alanine in some smaller vertebrate species (Chinese hamster, mouse). This variant is identified in 101 heterozygotes in gnomAD(v3.0), 0 homozygotes, with an allele frequency of 7.06e-4. In silico algorithms predict this variant to be Neutral (Provean; score:0.73) and Tolerated (SIFT; score:1.0) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:569422) and to our current knowledge has not been reported in affected individuals in the literature. The p.Val138 residue is not within a mapped domain of CIITA (UniProtKB:P33076). Given the lack of compelling evidence for its pathogenicity, the homozygous c.413T>C (p.Val138Ala) variant identified in the CIITA gene is reported as a Variant of Uncertain Significance.