Submissions for variant NM_001282531.3(ADNP):c.539_542del (p.Val180fs)

dbSNP: rs1057518345

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413777	SCV000491899	pathogenic	not provided	2020-05-12	criteria provided, single submitter	clinical testing	Reported previously in individuals with features suggestive of Helsmoortel-van der Aa syndrome, but limited information was provided on these individuals (Gozes et al., 2017; van Dijck et al., 2019; Bend et al., 2019); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 923 amino acids are lost and replaced with 16 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28221363, 29724491, 31029150, 32758449)
Ambry Genetics	RCV000622346	SCV000740905	pathogenic	Inborn genetic diseases	2015-06-10	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000626043	SCV000746661	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2017-08-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000626043	SCV001141253	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000626043	SCV001251635	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2020-02-27	criteria provided, single submitter	clinical testing	The ADNP c.539_542delTTAG (p.Val180GlyfsTer17) variant is a frameshift variant that has been identified in one study, in which it is found in a de novo heterozygous state in one individual with ADNP-related neurodevelopmental disorder (Bend et al. 2019). The p.Val180GlyfsTer17 variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the potential impact of truncating variants in this gene, its rarity, its identification in a patient in the literature, and application of the ACMG criteria, the p.Val180GlyfsTer17 variant is classified as pathogenic for ADNP-related neurodevelopmental disorder.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000413777	SCV001447513	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413777	SCV001502398	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ADNP: PS2, PVS1:Strong, PM2, PS4:Moderate
Daryl Scott Lab, Baylor College of Medicine	RCV000626043	SCV002515278	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2022-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV000413777	SCV003443840	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val180Glyfs*17) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 923 amino acid(s) of the ADNP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Helsmoortel-Van der Aa syndrome (PMID: 28675391, 31029150). ClinVar contains an entry for this variant (Variation ID: 373314). This variant disrupts a region of the ADNP protein in which other variant(s) (p.Tyr719*) have been determined to be pathogenic (PMID: 28221363, 28708303, 29911927). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000626043	SCV003836737	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2020-05-28	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, University of Torino	RCV000626043	SCV004171082	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder		criteria provided, single submitter	clinical testing