Submissions for variant NM_001282531.3(ADNP):c.2156dup (p.Tyr719Ter)

dbSNP: rs1135401808

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000170479	SCV000586774	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2017-01-06	criteria provided, single submitter	clinical testing	Intellectual disability, severe; antenatal cerebral ventriculomegaly; aggressive behaviour; small stature; probable neuropathy; stereotypies; dental disease; dysmorphism
GeneDx	RCV000627402	SCV000748396	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Ivashko-Pachima Y et al., 2019); Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 384 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 31332282, 28221363, 24531329, 29724491, 29911927, 28135719, 30679581, 31035039, 28708303, 31981491, 33673501, 31664177, 23160955, 31526516, 32758449, 32410215, 33004838, 24077912, 31785789)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000170479	SCV000965718	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2015-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000170479	SCV001141252	likely pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000627402	SCV001415712	pathogenic	not provided	2019-10-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ADNP protein function (PMID: 29911927). This variant has been observed in individual(s) with Helsmoortel-van der Aa syndrome (PMID: 28221363, 28708303). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190278). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the ADNP gene (p.Tyr719*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 384 amino acids of the ADNP protein.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000170479	SCV001440879	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000627402	SCV001446524	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV002277322	SCV002564466	pathogenic	Neurodevelopmental disorder	2021-12-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426805	SCV002727232	pathogenic	Inborn genetic diseases	2018-12-13	criteria provided, single submitter	clinical testing	The c.2156dupA pathogenic mutation, located in coding exon 3 of the ADNP gene, results from a duplication of A at nucleotide position 2156. This changes the amino acid from a tyrosine to a stop codon within coding exon 3 (p.Y719*). This mutation has been detected as de novo occurrences in multiple individuals in the literature with autism, various types of developmental delays, intellectual disability, and dysmorphic features (Gozes I et al. Transl Psychiatry, 2017 02;7:e1043; Gozes I et al. Front Endocrinol (Lausanne), 2017 May;8:107; Van Dijck A et al. Biol. Psychiatry, 2018 Mar; Helsmoortel C et al. Nat. Genet., 2014 Apr;46:380-4; Pescosolido MF et al. J. Med. Genet., 2014 Sep;51:587-9; O'Roak BJ et al. Science, 2012 Dec;338:1619-22; Chérot E et al. Clin. Genet., 2018 Mar;93:567-576).This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000170479	SCV000222906	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2015-03-12	no assertion criteria provided	literature only
Diagnostic Laboratory, Strasbourg University Hospital	RCV001249500	SCV001423490	pathogenic	Intellectual disability	2017-12-01	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000627402	SCV001807657	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000627402	SCV001970552	pathogenic	not provided		no assertion criteria provided	clinical testing