Submissions for variant NM_013275.6(ANKRD11):c.7535G>A (p.Arg2512Gln)

dbSNP: rs2033535934

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199356	SCV001370455	likely pathogenic	KBG syndrome	2019-06-23	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268505	SCV001447483	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268505	SCV001791039	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27605097, 26633542, 25413698)
3billion	RCV001199356	SCV002012212	pathogenic	KBG syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individuals (PMID: 25413698, PS2, PS4_M). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg2512Trp) has been reported as pathogenic (PMID: 25413698, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.834, 3Cnet: 0.888, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University Hospital Muenster	RCV003128563	SCV003804948	likely pathogenic	See cases	2023-01-05	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PM5,PP3,PP5,BP1
Ambry Genetics	RCV003373020	SCV004071546	pathogenic	Inborn genetic diseases	2023-08-30	criteria provided, single submitter	clinical testing	The c.7535G>A (p.R2512Q) alteration is located in exon 10 (coding exon 8) of the ANKRD11 gene. This alteration results from a G to A substitution at nucleotide position 7535, causing the arginine (R) at amino acid position 2512 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in two individuals with features consistent with KBG syndrome (Walz, 2015; de Boer, 2022). Two other alterations at the same codon, c.7534C>T (p.R2512W) and c.7535G>T (p.R2512L), have been described (de Boer, 2022). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This variant is indicated to disrupt a critical functional motif (Walz, 2015). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.