Submissions for variant NM_001282531.3(ADNP):c.2157C>G (p.Tyr719Ter)

dbSNP: rs587777526

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190684	SCV000244124	pathogenic	Inborn genetic diseases	2015-04-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000483727	SCV000567157	pathogenic	not provided	2022-06-20	criteria provided, single submitter	clinical testing	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); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29724491, 25057125, 28407407, 28221363, 24531329, 29911927, 29475819, 31785789, 33004838, 32758449, 31526516)
Illumina Laboratory Services, Illumina	RCV000128578	SCV002038512	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2021-10-01	criteria provided, single submitter	clinical testing	The ADNP c.2157C>G (p.Tyr719Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. This variant is located in the last exon and may escape nonsense-mediated decay. Across a selection of literature, the p.Tyr719Ter variant has been reported in a de novo heterozygous state in at least eight probands with a phenotype consistent with ADNP-related neurodevelopmental disorder (Helsmoortel et al. 2014; Pescosolido et al. 2014; Gozes et al. 2017). Van Dijck et al. 2019) noted that individuals with the p.Tyr719Ter variant walk later and have a higher pain threshold than individuals with other pathogenic ADNP variants. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggests the variant is rare. Based on the collective evidence, the p.Tyr719Ter variant is classified as pathogenic for ADNP-related neurodevelopmental disorder.
3billion	RCV000128578	SCV002058509	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 29724491, 24531329, PS4_S) and reported as de novo in a similarly affected individual (PMID: 24531329, PS2_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000139635, PMID:24531329). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000128578	SCV002768748	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.0, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected. (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0600 - Variant is located upstream of an annotated domain or motif (Homeodomain; NCBI, PDB). (N) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Deciphering Developmental Disorders Study, Helsmoortel, C. et al. (2014)). (P) 1102 - Strong phenotype match. (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P)
Invitae	RCV000483727	SCV003443958	pathogenic	not provided	2022-10-06	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: 139635). This premature translational stop signal 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. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr719*) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 384 amino acid(s) of the ADNP protein.
Revvity Omics, Revvity	RCV000128578	SCV003816653	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2022-04-27	criteria provided, single submitter	clinical testing
OMIM	RCV000128578	SCV000172226	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2014-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000128578	SCV000267170	not provided	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder		no assertion provided	literature only	Pathogenic variant in exon 4; associated with later onset of walking and higher pain threshold than other ADNP pathogenic variants
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000128578	SCV001427621	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2019-01-01	no assertion criteria provided	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000128578	SCV004032206	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder		no assertion criteria provided	research