NM_015443.4(KANSL1):c.2470C>T (p.Arg824Ter) AND Koolen-de Vries syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 8, 2023
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:: RCV003093950.4

Allele description [Variation Report for NM_015443.4(KANSL1):c.2470C>T (p.Arg824Ter)]

NM_015443.4(KANSL1):c.2470C>T (p.Arg824Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_015443.4(KANSL1):c.2470C>T (p.Arg824Ter)

Other names:

NM_015443.4(KANSL1):c.2470C>T; p.Arg824Ter

HGVS:

NC_000017.11:g.46038609G>A
NG_032784.1:g.191766C>T
NM_001193465.2:c.2470C>T
NM_001193466.2:c.2470C>T
NM_001379198.1:c.2470C>T
NM_015443.4:c.2470C>TMANE SELECT
NP_001180394.1:p.Arg824Ter
NP_001180395.1:p.Arg824Ter
NP_001366127.1:p.Arg824Ter
NP_056258.1:p.Arg824Ter
NC_000017.10:g.44115975G>A
NC_000017.10:g.44115975G>A
NM_001193466.1:c.2470C>T

Protein change:

R824*

Links:

dbSNP: rs2077221203

NCBI 1000 Genomes Browser:

rs2077221203

Molecular consequence:

NM_001193465.2:c.2470C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001193466.2:c.2470C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001379198.1:c.2470C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_015443.4:c.2470C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

Recent activity

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MULTISPECIES: hypothetical protein [Enterococcus]
MULTISPECIES: hypothetical protein [Enterococcus]
gi|488299756|ref|WP_002370964.1|

Protein
PREDICTED: Ornithorhynchus anatinus olfactory receptor 4D1-like (LOC100090878), ...
PREDICTED: Ornithorhynchus anatinus olfactory receptor 4D1-like (LOC100090878), mRNA
gi|1626049643|ref|XM_001519848.4|

Nucleotide
vacuolar protein sorting-associated protein 29 isoform X2 [Sceloporus undulatus]
vacuolar protein sorting-associated protein 29 isoform X2 [Sceloporus undulatus]
gi|2069507065|ref|XP_042298118.1|

Protein
cationic amino acid transporter 4 [Sceloporus undulatus]
cationic amino acid transporter 4 [Sceloporus undulatus]
gi|2069507077|ref|XP_042298124.1|

Protein
tRNA pseudouridine synthase Pus10 isoform X3 [Homo sapiens]
tRNA pseudouridine synthase Pus10 isoform X3 [Homo sapiens]
gi|2462570477|ref|XP_054196684.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003761212	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 24, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV004376684	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22544363, 22544367, 33393407, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003761212

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 24, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

SCV004376684

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 8, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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, curation

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

Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome.

Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, Toutain A, Amiel J, Malan V, Tsai AC, Cheung SW, Gilissen C, Verwiel ET, Martens S, Feuth T, Bongers EM, de Vries P, Scheffer H, Vissers LE, de Brouwer AP, Brunner HG, Veltman JA, et al.

Nat Genet. 2012 Apr 29;44(6):639-41. doi: 10.1038/ng.2262.

PubMed [citation]

PMID:: 22544363

See all PubMed Citations (5)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761212.1

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

Description

The heterozygous p.Arg824Ter variant in KANSL1 was identified by our study in one individual with Koolen de Vries syndrome. Trio exome analysis showed this variant to be de novo. This variant has been previously reported in one individual with Koolen de Vries syndrome, where it was found to be de novo (PMID: 33393407). This variant has also been reported in ClinVar (Variation ID# 1683960) and has been interpreted as pathogenic by GeneDx. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 824, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KANSL1 gene is an established disease mechanism in Koolen de Vries syndrome. In summary, this variant meets criteria to be classified as pathogenic for Koolen de Vries syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PM2_Supporting (Richards 2015).

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004376684.1

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

Description

This sequence change creates a premature translational stop signal (p.Arg824*) in the KANSL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KANSL1 are known to be pathogenic (PMID: 22544363, 22544367). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Koolen-de Vries syndrome (PMID: 33393407). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1683960). 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 13, 2024

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