Submissions for variant NM_013275.6(ANKRD11):c.6968_6975del (p.Ala2323fs)

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Minimum conflict level: Report conflict between different conditions
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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658333	SCV000780105	pathogenic	not provided	2023-09-23	criteria provided, single submitter	clinical testing	Frameshift 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: 31144778, 31209962)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691327	SCV000819103	pathogenic	KBG syndrome	2022-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 546454). This variant has not been reported in the literature in individuals affected with ANKRD11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala2323Glyfs*206) in the ANKRD11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANKRD11 are known to be pathogenic (PMID: 21782149, 25125236, 25413698, 25652421).
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000691327	SCV000999362	pathogenic	KBG syndrome		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000658333	SCV001446818	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000691327	SCV004847360	pathogenic	KBG syndrome	2024-03-22	criteria provided, single submitter	clinical testing	The p.Ala2323GlyfsX206 variant in ANKRD11 has been reported in at least 3 individuals with KBG syndrome, including 2 de novo occurrences (Carraro 2019 PMID: 31144778, Martinez-Cayuelas 2023 PMID: 36446582, ClinVar SCV: SCV000999362.1). It was also confirmed to be de novo by trio whole genome sequencing in a female with mild intellectual disability, short stature, short 5th digits, and dental abnormalities by the Broad Institute Rare Genomes Project. It was absent from large population studies, but has been reported in ClinVar (Variation ID 546454). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2323 and leads to a premature termination codon 206 amino acids downstream. Loss of function of the ANKRD11 gene is an established disease mechanism in autosomal dominant KBG syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant KBG syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PM2_Supporting.

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