NM_015443.4(KANSL1):c.954A>T (p.Gln318His) AND Koolen-de Vries syndrome

Clinical significance:Uncertain significance (Last evaluated: Oct 21, 2021)
Review status:2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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Based on:: 2 submissions [Details]
Record status:: current
Accession:: RCV001978019.2

Allele description [Variation Report for NM_015443.4(KANSL1):c.954A>T (p.Gln318His)]

NM_015443.4(KANSL1):c.954A>T (p.Gln318His)

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.954A>T (p.Gln318His)

HGVS:

NC_000017.11:g.46171190T>A
NG_032784.1:g.59185A>T
NM_001193465.2:c.954A>T
NM_001193466.2:c.954A>T
NM_001379198.1:c.954A>T
NM_015443.4:c.954A>TMANE SELECT
NP_001180394.1:p.Gln318His
NP_001180395.1:p.Gln318His
NP_001366127.1:p.Gln318His
NP_056258.1:p.Gln318His
NC_000017.10:g.44248556T>A

Protein change:

Q318H

Molecular consequence:

NM_001193465.2:c.954A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001193466.2:c.954A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379198.1:c.954A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015443.4:c.954A>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002262708	Invitae	criteria provided, single submitter Invitae Variant Classification Sherloc (09022015)	Uncertain significance (Jul 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002792764	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter ACMG Guidelines, 2015	Uncertain significance (Oct 21, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002262708

Invitae

criteria provided, single submitter

Invitae Variant Classification Sherloc (09022015)

Uncertain significance
(Jul 1, 2021)

germline

clinical testing

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

SCV002792764

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

ACMG Guidelines, 2015

Uncertain significance
(Oct 21, 2021)

unknown

clinical testing

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

Summary from all submissions

Help

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

Details of each submission

From Invitae, SCV002262708.1

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

Description

Due to the possible presence of a polymorphic segmental duplication, the location of the variant could not be unambiguously resolved. Variants with ambiguous mapping are still reported relative to the KANSL1 transcript. This sequence change replaces glutamine with histidine at codon 318 of the KANSL1 protein (p.Gln318His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with KANSL1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Until the location of this sequence change can be resolved, the clinical significance of this variant remains uncertain. It has been classified as a Variant of Uncertain Significance.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002792764.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 7, 2023

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