Submissions for variant NM_013275.6(ANKRD11):c.2398_2401del (p.Glu800fs)

dbSNP: rs797045027

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191060	SCV000245449	pathogenic	KBG syndrome	2012-07-27	criteria provided, single submitter	clinical testing	This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory de novo in a 20-year-old female with intellectual disability, mild unilateral hearing loss, ptosis, Marcus Gunn pupil, short stature, scoliosis, wrinkled palms, dysmorphisms
GeneDx	RCV000255252	SCV000322338	pathogenic	not provided	2021-11-09	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31703437, 31401500, 32124548, 27605097, 25464108, 27479843, 28135719, 31216405, 26633545, 33955014, 34387732)
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000191060	SCV000803683	pathogenic	KBG syndrome	2017-08-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255252	SCV001335049	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266330	SCV001444504	pathogenic	Inborn genetic diseases	2022-09-27	criteria provided, single submitter	clinical testing	The c.2398_2401delGAAA (p.E800Nfs*62) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 4 nucleotides from position 2398 to 2401, causing a translational frameshift with a predicted alternate stop codon after 62 amino acids. 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 reported as a de novo mutation in multiple unrelated individuals with clinical features of KBG syndrome (Goldenberg, 2016; Gao, 2022). In addition, it has been found to segregate with disease in one family (Kim, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000255252	SCV001446659	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Human Genetics, University Hospital Essen	RCV001376674	SCV001478033	pathogenic	Global developmental delay	2021-01-22	criteria provided, single submitter	research
Blueprint Genetics	RCV000255252	SCV001832381	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000191060	SCV001870353	pathogenic	KBG syndrome	2021-03-29	criteria provided, single submitter	research	ACMG codes:PVS1, PS4M, PP5
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano	RCV000191060	SCV002097371	pathogenic	KBG syndrome	2021-11-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000191060	SCV002239706	pathogenic	KBG syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu800Asnfs*62) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with KBG syndrome (PMID: 25464108, 27605097). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209131). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000191060	SCV002767294	pathogenic	KBG syndrome	2021-05-06	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) 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. These variants are often de novo, and have been reported many times as pathogenic in individuals with KBG syndrome (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has arisen de novo in multiple individuals with KBG syndrome. It has also been reported to segregate within a family with KBG syndrome (ClinVar, Decipher, PMID: 25464108, PMID: 27605097). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000191060	SCV004847308	pathogenic	KBG syndrome	2023-08-16	criteria provided, single submitter	clinical testing	The p.Glu800AsnfsX62 (c.2398_2401delGAAA) variant in ANKRD11 has been reported in 5 probands with KBG syndrome, including as a de novo variant in 2 probands (Goldenberg 2016 PMID: 27605097, Gao 2022 PMID: 35330407, Kim 2015 PMID: 25464108, Parenti 2021 PMID: 33955014, Bestetti 2022 PMID: 35682590). Additionally, it segregated with disease in 3 affected individuals from 2 families (Kim 2015 PMID: 25464108, Parenti 2021 PMID: 33955014). This variant is absent from large population studies (gnomAD v3.2.1, http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID: 209131). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 800 and leads to a premature termination codon 62 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of ANKRD11 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, PS4, PM6_Strong, PM2_Supporting, PP1.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000191060	SCV005417517	pathogenic	KBG syndrome		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Moderate+PP1+PP4
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001256986	SCV001433532	pathogenic	Rare genetic intellectual disability		no assertion criteria provided	clinical testing
Autoinflammatory diseases unit, CHU de Montpellier	RCV000191060	SCV001438087	pathogenic	KBG syndrome	2017-05-18	no assertion criteria provided	clinical testing
GenomeConnect - Simons Searchlight	RCV000191060	SCV001443473	pathogenic	KBG syndrome	2018-03-02	no assertion criteria provided	provider interpretation	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-03-02 and interpreted as Pathogenic. Variant was initially reported on 2017-09-23 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar.