Submissions for variant NM_013275.6(ANKRD11):c.2684G>A (p.Arg895Gln)

gnomAD frequency: 0.00014  dbSNP: rs199800166

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493061	SCV000583171	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing	Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30919572, 27535533)
Invitae	RCV000696596	SCV000825161	uncertain significance	KBG syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 895 of the ANKRD11 protein (p.Arg895Gln). This variant is present in population databases (rs199800166, gnomAD 0.003%). This missense change has been observed in individual(s) with intellectual disability, ataxia and dismorphic facial features (PMID: 30919572). ClinVar contains an entry for this variant (Variation ID: 430379). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANKRD11 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV002318599	SCV000850840	likely benign	Inborn genetic diseases	2017-12-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
PreventionGenetics, part of Exact Sciences	RCV003424046	SCV004117311	uncertain significance	ANKRD11-related condition	2022-09-26	criteria provided, single submitter	clinical testing	The ANKRD11 c.2684G>A variant is predicted to result in the amino acid substitution p.Arg895Gln. This variant was reported as likely pathogenic in a male patient with intellectual disability, speech delay, ataxia, and dysmorphic facial features including high nasal bridge and prominent chin (Table S1 & S3, Al-Dewik et al 2019. PubMed ID: 30919572). However, conclusive evidence of pathogenicity was not presented. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89350266-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.