Submissions for variant NM_013275.6(ANKRD11):c.3770_3771del (p.Lys1257fs)

dbSNP: rs886039477

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256105	SCV000322085	pathogenic	not provided	2021-11-10	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: 28529015, 31703437, 32124548, 25326635, 28135719)
Ambry Genetics	RCV000622880	SCV000740977	pathogenic	Inborn genetic diseases	2022-06-21	criteria provided, single submitter	clinical testing	The c.3770_3771delAA (p.K1257Rfs*25) alteration, located in exon 9 (coding exon 7) of the ANKRD11 gene, consists of a deletion of 2 nucleotides from position 3770 to 3771, causing a translational frameshift with a predicted alternate stop codon after 25 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 alteration has been reported as a de novo event in multiple unrelated individuals with KBG syndrome (Meyer, 2017; Gnazzo, 2020). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000679885	SCV000807284	pathogenic	KBG syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our laboratory as a de novo finding in a 4-year-old female with delays, hypotonia, anxiety, short stuture, atrial septal defect.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000256105	SCV001450109	likely pathogenic	not provided	2015-01-19	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000679885	SCV001622826	pathogenic	KBG syndrome	2020-05-15	criteria provided, single submitter	clinical testing	The de novo c.3770_3771del (p.Lys1257ArgfsTer25) variant identified in the ANKRD11 gene is the deletion of two nucleotides, resulting in the frameshift of the amino acid 1257/2664 (coding exon 9/13), and is predicted to lead to the premature termination of the protein approximately 25 amino acids downstream of the frameshift. This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported in ClinVar as Pathogenic (VarID: 265324) by two independent clinical labs who state the variant was identified de novo in affected individuals. The c.3770_3771del (p.Lys1257ArgfsTer25) variant has also been reported in the literature in a male with feeding difficulties, short stature, hyperopic astigmatism, hearing loss, and Autism Spectrum Disorder [PMID:28529015], and a female with KBG syndrome [PMID:31703437]. Given its presence de novo in this individual, its deleterious nature, absence in population databases, and observation in multiple affected individuals in the literature, the c.3770_3771del (p.Lys1257ArgfsTer25) variant identified in the ANKRD11 gene is reported here as Pathogenic.
Genome Medicine, Institute for Basic Research in Developmental Disabilities	RCV000679885	SCV002562750	pathogenic	KBG syndrome		criteria provided, single submitter	clinical testing	KBG syndrome
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000679885	SCV003807361	pathogenic	KBG syndrome	2022-07-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM6 moderated
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001257013	SCV001433569	likely pathogenic	Rare genetic intellectual disability		no assertion criteria provided	clinical testing
Autoinflammatory diseases unit, CHU de Montpellier	RCV000679885	SCV005381973	pathogenic	KBG syndrome	2024-06-24	no assertion criteria provided	clinical testing