Submissions for variant NM_017721.5(CC2D1A):c.2657G>A (p.Arg886His)

gnomAD frequency: 0.00072  dbSNP: rs201921029

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502989	SCV000593883	uncertain significance	not specified	2016-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV000892683	SCV001036576	uncertain significance	not provided	2022-06-23	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 886 of the CC2D1A protein (p.Arg886His). This variant is present in population databases (rs201921029, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features CC2D1A-related conditions (PMID: 27799067). ClinVar contains an entry for this variant (Variation ID: 254203). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; 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.
CeGaT Center for Human Genetics Tuebingen	RCV000892683	SCV001249846	uncertain significance	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267084	SCV001445265	uncertain significance	Inborn genetic diseases	2019-07-12	criteria provided, single submitter	clinical testing	The p.R886H variant (also known as c.2657G>A), located in coding exon 26 of the CC2D1A gene, results from a G to A substitution at nucleotide position 2657. The arginine at codon 886 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001333956	SCV001526675	uncertain significance	Intellectual disability, autosomal recessive 3	2018-07-11	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000892683	SCV001989074	uncertain significance	not provided	2022-09-29	criteria provided, single submitter	clinical testing	Observed with an additional missense variant in a patient with developmental delay, behavior problems, and dysmorphic features in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Loviglio et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27799067)
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000491719	SCV000299210	pathogenic	Smith-Magenis Syndrome-like	2016-08-15	flagged submission	research