Submissions for variant NM_013275.6(ANKRD11):c.2692C>T (p.Arg898Ter)

dbSNP: rs780011005

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760640	SCV000890532	pathogenic	not provided	2023-01-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34803598, 33955014)
Institute for Human Genetics, University Hospital Essen	RCV001376676	SCV001478035	pathogenic	Global developmental delay	2021-01-22	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001388447	SCV001589445	pathogenic	KBG syndrome	2020-08-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg898*) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs780011005, ExAC 0.009%). This variant has not been reported in the literature in individuals with ANKRD11-related conditions. ClinVar contains an entry for this variant (Variation ID: 620276). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25125236, 25413698, 25652421). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001388447	SCV003932284	pathogenic	KBG syndrome	2023-02-02	criteria provided, single submitter	clinical testing	PVS1, PS2, PS4_Supporting, PM2
PreventionGenetics, part of Exact Sciences	RCV004723158	SCV005337305	pathogenic	ANKRD11-related disorder	2024-04-22	no assertion criteria provided	clinical testing	The ANKRD11 c.2692C>T variant is predicted to result in premature protein termination (p.Arg898*). This variant was reported to be de novo in an individual with features consistent with KBG syndrome (Parenti et al. 2021. PubMed ID: 33955014). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in ANKRD11 are expected to be pathogenic. This variant is interpreted as pathogenic.