Submissions for variant NM_001006658.3(CR2):c.2030C>T (p.Thr677Met)

gnomAD frequency: 0.00049  dbSNP: rs142648420

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768193	SCV000898635	uncertain significance	Systemic lupus erythematosus, susceptibility to, 9; Immunodeficiency, common variable, 7		criteria provided, single submitter	clinical testing	CR2 NM_001006658 exon 11 p.Thr677Met (c.2030C>T): This variant has not been reported in the literature but is present in 0.1% (40/24030) of African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs142648420). This variant amino acid Methionine (Met) is present in several species 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855719	SCV002110291	uncertain significance	Immunodeficiency, common variable, 7	2022-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 677 of the CR2 protein (p.Thr677Met). This variant is present in population databases (rs142648420, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 626091). 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 methionine 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.
Genome-Nilou Lab	RCV001855719	SCV004180432	uncertain significance	Immunodeficiency, common variable, 7	2023-04-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV005318517	SCV005986743	likely benign	Inborn genetic diseases	2025-01-18	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.