NM_001282531.3(ADNP):c.539_542del (p.Val180fs) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000413777.28

Allele description [Variation Report for NM_001282531.3(ADNP):c.539_542del (p.Val180fs)]

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

Gene:

ADNP:activity dependent neuroprotector homeobox [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

20q13.13

Genomic location:

Preferred name:

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

HGVS:

NC_000020.10:g.49510709_49510712del
NC_000020.11:g.50894175_50894178del
NG_034200.1:g.41816_41819del
NM_001282531.3:c.539_542delMANE SELECT
NM_001282532.2:c.539_542del
NM_001347511.2:c.539_542del
NM_015339.5:c.539_542del
NM_181442.4:c.539_542del
NP_001269460.1:p.Val180fs
NP_001269461.1:p.Val180fs
NP_001334440.1:p.Val180fs
NP_056154.1:p.Val180fs
NP_852107.1:p.Val180fs
NC_000020.10:g.49510709_49510712del
NC_000020.10:g.49510709_49510712delCTAA
NC_000020.10:g.49510712_49510715del
NM_001282531.2:c.539_542del
NM_001282531.2:c.539_542delTTAG
NM_001282531.3:c.539_542del
NM_015339.2:c.539_542del
NM_015339.2:c.539_542delTTAG
p.V180fs

Protein change:

V180fs

Links:

dbSNP: rs1057518345

NCBI 1000 Genomes Browser:

rs1057518345

Molecular consequence:

NM_001282531.3:c.539_542del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001282532.2:c.539_542del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001347511.2:c.539_542del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015339.5:c.539_542del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_181442.4:c.539_542del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000491899	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 19, 2024)	germline	clinical testing	Citation Link,
SCV001447513	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001502398	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2024)	germline	clinical testing	Citation Link,
SCV003443840	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28675391, 31029150, 28221363, 28708303, 29911927, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children.

Gozes I, Van Dijck A, Hacohen-Kleiman G, Grigg I, Karmon G, Giladi E, Eger M, Gabet Y, Pasmanik-Chor M, Cappuyns E, Elpeleg O, Kooy RF, Bedrosian-Sermone S.

Transl Psychiatry. 2017 Jul 4;7(7):e1166. doi: 10.1038/tp.2017.128.

PubMed [citation]

PMID:: 28675391
PMCID:: PMC5538113

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000491899.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Frameshift variant predicted to result in abnormal protein length as the last 923 amino acids are replaced with 16 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29724491, 31029150, 35904121, 33860439, 35982159, 31785789, 36474027, 32758449, 31526516, Aspromonte2023[pre-print], 36553633, 28221363)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447513.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001502398.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

ADNP: PS2, PVS1:Strong, PM2, PS4:Moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443840.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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