Submissions for variant NM_001282531.3(ADNP):c.2491_2494del (p.Leu831fs)

dbSNP: rs587777522

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485997	SCV000564547	pathogenic	not provided	2021-11-05	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 272 amino acids are lost and replaced with 81 incorrect amino acids (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24531329, 28221363, 28475273, 29724491, 27054228, 31785789, 30929737, 31029150, 33004838)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526522	SCV001736944	pathogenic	Intellectual disability		criteria provided, single submitter	clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV000128574	SCV002577706	likely pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2022-10-04	criteria provided, single submitter	clinical testing	PVS1_strong;PS4_moderate;PM6;PM2_supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000485997	SCV004298098	pathogenic	not provided	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu831Ilefs*82) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 272 amino acid(s) of the ADNP protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autism (PMID: 24531329). ClinVar contains an entry for this variant (Variation ID: 139631). This variant disrupts a region of the ADNP protein in which other variant(s) (p.Met1088Serfs*5) have been determined to be pathogenic (PMID: 28135719). 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.
Ambry Genetics	RCV004019727	SCV004866160	pathogenic	Inborn genetic diseases	2024-01-11	criteria provided, single submitter	clinical testing	The c.2491_2494delTTAA (p.L831Ifs*82) alteration, located in exon 5 (coding exon 3) of the ADNP gene, consists of a deletion of 4 nucleotides from position 2491 to 2494, causing a translational frameshift with a predicted alternate stop codon after 82 amino acids. This alteration occurs at the 3' terminus of the ADNP gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 24.5% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/251336) total alleles studied. The highest observed frequency was 0.001% (1/113634) of European (non-Finnish) alleles. This variant was reported in multiple individuals with autism and other features consistent with ADNP-related neurodevelopmental disorder, and has been reported de novo in other individuals with similar clinical features (Helsmoortel, 2014; Li, 2017; Aref-Eshghi, 2019; Van Dijck, 2019). Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000128574	SCV000172222	pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2014-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000128574	SCV000267171	not provided	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder		no assertion provided	literature only	All other pathogenic variants are heterozygous frameshift or nonsense variants in the 3-prime end of 5th (last) exon of ADNP and predict a premature termination