NM_015443.4(KANSL1):c.985_986del (p.Leu329fs) AND Koolen-de Vries syndrome

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jun 25, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000032181.8

Allele description [Variation Report for NM_015443.4(KANSL1):c.985_986del (p.Leu329fs)]

NM_015443.4(KANSL1):c.985_986del (p.Leu329fs)

Gene:

KANSL1:KAT8 regulatory NSL complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_015443.4(KANSL1):c.985_986del (p.Leu329fs)

HGVS:

NC_000017.11:g.46171159_46171160del
NG_032784.1:g.59216_59217del
NM_001193465.2:c.985_986del
NM_001193466.2:c.985_986del
NM_001379198.1:c.985_986del
NM_015443.4:c.985_986delMANE SELECT
NP_001180394.1:p.Leu329fs
NP_001180395.1:p.Leu329fs
NP_001366127.1:p.Leu329fs
NP_056258.1:p.Leu329fs
NC_000017.10:g.44248525_44248526del
NC_000017.11:g.46171158_46171159delAA
NM_001193466.1:c.985_986delTT

Protein change:

L329fs

Links:

OMIM: 612452.0005; dbSNP: rs281865473

NCBI 1000 Genomes Browser:

rs281865473

Molecular consequence:

NM_001193465.2:c.985_986del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001193466.2:c.985_986del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001379198.1:c.985_986del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015443.4:c.985_986del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Koolen-de Vries syndrome (KDVS)
Synonyms:: KANSL1-Related Intellectual Disability Syndrome
Identifiers:: MONDO: MONDO:0012496; MedGen: C1864871; Orphanet: 96169; OMIM: 610443

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000055765	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV000677104	OMIM	no assertion criteria provided	Pathogenic (Oct 2, 2024)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000807287	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 1, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 25326635
SCV002516587	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV005061832	Genomic Medicine, Universita Cattolica del Sacro Cuore	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jun 25, 2024)	paternal, maternal, de novo, not applicable	clinical testing, in vitro	PubMed (2) [See all records that cite these PMIDs] 33050294, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	no	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	no	1	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	no	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro

Citations

PubMed

Koolen-de Vries Syndrome..

Koolen DA, Morgan A, de Vries BBA.

2010 Jan 26 [updated 2023 Feb 2]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

PubMed [citation]

PMID:: 20301783

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.

Koolen DA, Pfundt R, Linda K, Beunders G, Veenstra-Knol HE, Conta JH, Fortuna AM, Gillessen-Kaesbach G, Dugan S, Halbach S, Abdul-Rahman OA, Winesett HM, Chung WK, Dalton M, Dimova PS, Mattina T, Prescott K, Zhang HZ, Saal HM, Hehir-Kwa JY, Willemsen MH, Ockeloen CW, et al.

Eur J Hum Genet. 2016 May;24(5):652-9. doi: 10.1038/ejhg.2015.178. Epub 2015 Aug 26.

PubMed [citation]

PMID:: 26306646
PMCID:: PMC4930086

See all PubMed Citations (5)

Details of each submission

From GeneReviews, SCV000055765.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

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

From OMIM, SCV000677104.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 5-year-old boy (patient 36) with Koolen-de Vries syndrome (KDVS; 610443), Koolen et al. (2016) identified a de novo heterozygous 2-bp deletion (c.985_986del, NM_001193466.1) in exon 2 of the KANLS1 gene, predicted to result in a frameshift and premature termination (Leu329GlufsTer22).

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

From Baylor Genetics, SCV000807287.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (2)

Description

Likely pathogenicity based on finding it twice in our laboratory: in a 7-year-old male with intellectual disability, dysmorphisms, short stature, strabismus, asymmetric prominent ventricles, possible undermylination, amygdala/hippocampal dysgenesis; in a 3-year-old feale with global delays, hypotonia, dysmorphisms, short stature, microcephaly, congenital heart disease, brain & eye anomalies. However, inheritance was not determined, and of note, the promoter and 5' exons of KANSL1 can be partially duplicated in some individuals. Exome and Sanger data could not distinguish if this change is located in the real KANSL1 gene or the duplicated copy of the gene

#	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	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Mendelics, SCV002516587.1

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

#	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

From Genomic Medicine, Universita Cattolica del Sacro Cuore, SCV005061832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (2)
2		1	not provided	not provided	clinical testing	PubMed (2)
3		1	not provided	not provided	clinical testing	PubMed (2)
4	not provided	not provided	not provided	not provided	in vitro	PubMed (2)

Description

The patient underwent exome sequencing for idiopathic developmental delay and this variant was identified.

The patient underwent exome sequencing for idiopathic developmental delay and this variant was identified

The patient underwent exome sequencing for idiopathic developmental delay and this variant was identified.

Description

Inherited from healthy father. Patient lacking Koolen-de Vries syndrome (KdVS) phenotype. By cDNA analysis, it has been demonstrated that the variant involves a non-functional KANSL1 pseudogene that can be found in some structural haplotypes (PMID: 22751100, PMID: 22751096, PMID: 33050294). IMPORTANT: this variant has been classified as benign in this case because it affects neither functional allele of the KANSL1 gene. it, instead, involves a duplicated genomic region that includes the first two (or three) exons of the KANSL1 transcript NM_015443.4. On the contrary, it should have been considered pathogenic if it was mapped within either functional copy of the KANSL1 gene (PMID: 26306646). It is not possible to define if the variant affects the duplicated region or the functional KANSL1 gene sequence solely on the basis of genomic DNA sequencing results. This variant is reported in the gnomAD database v4.1.0 with a frequency of 0.000005085 in non-Finnish European population (6 out of 1180044 alleles) and of 0.0002702 (8 out of 29606 alleles) in Ashkenazi Jewish population. We expect it is mismapped in those subjects (who are supposed not to be affected by KdVS) and involves the polymorphic duplication of KANSL1 exon 2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	no	not provided	not provided	not provided		1	not provided	not provided	not provided
2	maternal	no	not provided	not provided	not provided		1	not provided	not provided	not provided
3	de novo	no	not provided	not provided	not provided		1	not provided	not provided	not provided
4	not applicable	not applicable	not provided	Peripheral blood	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 28, 2024

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