Submissions for variant NM_013275.6(ANKRD11):c.1903_1907del (p.Lys635fs)

dbSNP: rs886041125

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000406838	SCV000329064	pathogenic	not provided	2022-02-24	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: 27605097, 25833229, 28191890, 29158550, 32581362, 25413698, 25424714, 27667800, 25533962, 25363768, 28250421, 28449295, 28135719, 29530238, 31332282, 33048330, 32124548, 32371413, 31981491, 33955014, 33767182)
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000496332	SCV000586701	pathogenic	KBG syndrome	2017-08-01	criteria provided, single submitter	clinical testing	De novo LOF variant in a patient with feeding difficulties, short stature, microcephaly, moderate to severe ID, facial freckling.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000496332	SCV000598143	pathogenic	KBG syndrome	2016-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624014	SCV000741382	pathogenic	Inborn genetic diseases	2016-03-30	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626912	SCV000747615	likely pathogenic	Global developmental delay; Ptosis; Clinodactyly of the 5th finger; Conductive hearing impairment; Intellectual disability; Short foot; Short palm; Unilateral cryptorchidism	2017-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000496332	SCV000807329	pathogenic	KBG syndrome	2021-09-20	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000496332	SCV001167576	pathogenic	KBG syndrome	2018-03-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496332	SCV001222998	pathogenic	KBG syndrome	2024-06-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys635Glnfs*26) 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: 25533962, 25833229, 27605097, 27667800, 28250421, 28449295; Invitae). 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: 279678). For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000496332	SCV001423630	pathogenic	KBG syndrome	2019-03-11	criteria provided, single submitter	clinical testing	[ACMG/AMP: PVS1, PS2, PM2, PS4_Moderate, PP1, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], has been shown to cosegregate with disease in multiple affected family members [PP1], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Institute of Human Genetics, University of Leipzig Medical Center	RCV000496332	SCV001429285	pathogenic	KBG syndrome	2019-06-05	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000406838	SCV001446926	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000496332	SCV001449014	pathogenic	KBG syndrome	2019-07-08	criteria provided, single submitter	clinical testing
Institute for Human Genetics, University Hospital Essen	RCV001376679	SCV001478038	pathogenic	Global developmental delay	2021-01-22	criteria provided, single submitter	research
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001249513	SCV001593256	pathogenic	Intellectual disability	2021-05-12	criteria provided, single submitter	clinical testing	de novo truncating variant absent from gnomAD. ALready pathogenic in ClinVar
CeGaT Center for Human Genetics Tuebingen	RCV000406838	SCV001747176	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	ANKRD11: PS2:Very Strong, PVS1, PM2, PS4:Moderate
Genomics England Pilot Project, Genomics England	RCV000496332	SCV001760384	pathogenic	KBG syndrome		criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000406838	SCV001832255	pathogenic	not provided	2019-09-23	criteria provided, single submitter	clinical testing
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano	RCV000496332	SCV002097368	pathogenic	KBG syndrome	2021-11-01	criteria provided, single submitter	research
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002274005	SCV002558912	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
3billion	RCV000496332	SCV002573020	pathogenic	KBG syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17325136). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.69 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099217 /PMID: 9781034).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 17325136, 19365591, 29925512, 30093795). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000496332	SCV002580668	pathogenic	KBG syndrome	2022-02-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000496332	SCV003807633	pathogenic	KBG syndrome	2022-10-21	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting, PM6 moderated
Revvity Omics, Revvity	RCV000496332	SCV003817385	pathogenic	KBG syndrome	2021-12-27	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000496332	SCV004046188	pathogenic	KBG syndrome		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 9 of 13 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a heterozygous familial and de novo change in patients with KBG syndrome (PMID: 27667800, 28449295, 27605097, 25533962, 28250421). The c.1903_1907del (p.Lys635GlnfsTer26) variant is absent from the gnomAD population database and thus is presumed to be rare. This result was confirmed by orthogonal testing. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1903_1907del (p.Lys635GlnfsTer26) variant is classified as Pathogenic.
Laboratory of Medical Genetics, University of Torino	RCV000496332	SCV004171097	pathogenic	KBG syndrome		criteria provided, single submitter	clinical testing
Molecular Genetics Lab, CHRU Brest	RCV000496332	SCV004697661	pathogenic	KBG syndrome		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000496332	SCV005086438	pathogenic	KBG syndrome	2023-07-17	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. Intrafamilial variability is commonly 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) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than ten individuals, including de novo events (ClinVar, DECIPHER, PMID: 36446582). (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
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000406838	SCV005198328	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000496332	SCV005420481	pathogenic	KBG syndrome	2024-10-04	criteria provided, single submitter	research	PVS1,PS2,PM2,PP1
Daryl Scott Lab, Baylor College of Medicine	RCV000496332	SCV005871314	pathogenic	KBG syndrome	2024-01-01	criteria provided, single submitter	clinical testing	PVS1, PS2, PS4, PM2, PP1
Center of Human Genetics, Hôpital Erasme	RCV000496332	SCV006076637	pathogenic	KBG syndrome	2025-01-01	criteria provided, single submitter	clinical testing
GeneReviews	RCV000496332	SCV000778368	not provided	KBG syndrome		no assertion provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003618	SCV001162029	pathogenic	Global developmental delay; Seizure; Abnormal facial shape; Conductive hearing impairment; Delayed speech and language development		no assertion criteria provided	research
Diagnostic Laboratory, Strasbourg University Hospital	RCV001249513	SCV001423503	pathogenic	Intellectual disability	2016-12-01	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001256985	SCV001433531	pathogenic	Rare genetic intellectual disability		no assertion criteria provided	clinical testing
Autoinflammatory diseases unit, CHU de Montpellier	RCV000496332	SCV001438084	pathogenic	KBG syndrome	2014-12-15	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000496332	SCV001450672	pathogenic	KBG syndrome	2020-08-31	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000496332	SCV002583321	pathogenic	KBG syndrome	2021-11-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739647	SCV005355457	pathogenic	ANKRD11-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The ANKRD11 c.1903_1907del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys635Glnfs*26). This variant has been reported as a recurrent causative variant for KBG Syndrome (Walz et al. 2015. PubMed ID: 25413698; Low et al. 2016. PubMed ID: 27667800; Miyatake et al. 2017. PubMed ID: 28250421; Gnazzo et al. 2020. PubMed ID: 32124548). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in ANKRD11 are expected to be pathogenic. This variant is interpreted as pathogenic.