Submissions for variant NM_013275.6(ANKRD11):c.1801C>T (p.Arg601Ter)

dbSNP: rs772229371

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000317010	SCV000330108	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	Identified in patients with features of ANKRD11-related KBG syndrome in published literature, including as a de novo variant with confirmed parentage (PMID: 25533962, 27667800); 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: 25533962, 27667800, 28191890, 28135719)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001251665	SCV003522003	pathogenic	KBG syndrome	2022-06-02	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: 280209). This premature translational stop signal has been observed in individual(s) with ANKRD11-related conditions (PMID: 25533962, 27667800). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg601*) 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).
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001251665	SCV004810256	pathogenic	KBG syndrome	2024-04-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001251665	SCV005086819	pathogenic	KBG syndrome	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with KBG syndrome (MIM#148050). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported (PMID: 29258554). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple de novo individuals with KBG syndrome (ClinVar, DECIPHER, PMID: 35330407). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004649114	SCV005142020	pathogenic	Inborn genetic diseases	2024-04-15	criteria provided, single submitter	clinical testing	The c.1801C>T (p.R601*) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a C to T substitution at nucleotide position 1801. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 601. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 (Deciphering Developmental Disorders, 2015; Rastogi, 2022). Based on the available evidence, this alteration is classified as pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251665	SCV001427405	pathogenic	KBG syndrome	2019-01-01	no assertion criteria provided	clinical testing