Submissions for variant NM_001282531.3(ADNP):c.3047dup (p.Ala1017fs)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003227102	SCV003923358	uncertain significance	not provided	2024-06-18	criteria provided, single submitter	clinical testing	Observed in large scale studies of individuals with autism or unspecified developmental disorders in the published literature (PMID: 29724491, 33004838); Frameshift variant predicted to result in protein truncation as the last 86 amino acids are lost and replaced with 5 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27308845, 33004838, 29724491, 37506195, 30564305, 28135719)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388217	SCV004099722	likely pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: ADNP c.3047dupA (p.Ala1017GlyfsX6) results in a premature termination codon in the last exon, therefore it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein (removing the C-terminal part of the 1102 amino acid long protein). Truncations downstream from this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 1.6e-05 in 248546 control chromosomes in the gnomAD database, exomes dataset (i.e. 4 / 248546 alleles, however these four samples didn't pass the quality filters, therefore the occurrence data might not be reliable). The variant, c.3047dupA, has been reported in the literature in individuals affected with ADNP-Related Multiple Congenital Anomalies-Intellectual Disability-Autism Spectrum Disorder (e.g. Guo_2018, VanDijck_2018, Wang_2020), and in multiple cases the variant was noted to be inherited from an apparently unaffected parent, or from a parent with milder phenotype. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30564305, 29724491, 33004838). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003227102	SCV004539098	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 2501307). This premature translational stop signal has been observed in individual(s) with clinical features of Helsmoortel-Van der Aa syndrome (PMID: 29724491, 33004838). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala1017Glyfs*6) in the ADNP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acid(s) of the ADNP protein.
Neuberg Centre For Genomic Medicine, NCGM	RCV003388217	SCV005329451	likely pathogenic	ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder	2023-05-20	criteria provided, single submitter	clinical testing	The observed frameshift variant c.3047dup(p.Ala1017GlyfsTer6) in the ADNP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.002% in the gnomAD Exomes. This variant causes a frameshift starting with codon Alanine 1017, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Ala1017GlyfsTer6. Though this variant is present in the last exon, there are three heterozygous variants reported beyond this position in the ClinVar database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Van Dijck A, et al., 2019). For these reasons, this variant has been classified as Likely Pathogenic.