NM_031263.4(HNRNPK):c.253G>A (p.Glu85Lys) AND Au-Kline syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 1, 2022
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:: RCV000627090.5

Allele description

NM_031263.4(HNRNPK):c.253G>A (p.Glu85Lys)

Genes:

HNRNPK-AS1:HNRNPK antisense RNA 1 [Gene - HGNC]
HNRNPK:heterogeneous nuclear ribonucleoprotein K [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q21.32

Genomic location:

Preferred name:

NM_031263.4(HNRNPK):c.253G>A (p.Glu85Lys)

HGVS:

NC_000009.12:g.83975466C>T
NG_029577.1:g.10189G>A
NM_001318186.2:c.253G>A
NM_001318187.2:c.253G>A
NM_001318188.2:c.253G>A
NM_002140.5:c.253G>A
NM_031262.4:c.253G>A
NM_031263.4:c.253G>AMANE SELECT
NP_001305115.1:p.Glu85Lys
NP_001305116.1:p.Glu85Lys
NP_001305117.1:p.Glu85Lys
NP_002131.2:p.Glu85Lys
NP_002131.2:p.Glu85Lys
NP_112552.1:p.Glu85Lys
NP_112553.1:p.Glu85Lys
NC_000009.11:g.86590381C>T
NM_002140.3:c.253G>A
NM_002140.4:c.253G>A

Protein change:

E85K; GLU85LYS

Links:

OMIM: 600712.0006; dbSNP: rs1554700678

NCBI 1000 Genomes Browser:

rs1554700678

Molecular consequence:

NM_001318186.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318187.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318188.2:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002140.5:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_031262.4:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_031263.4:c.253G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Au-Kline syndrome
Synonyms:: Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome due to a point mutation
Identifiers:: MONDO: MONDO:0014700; MedGen: C4225274; Orphanet: 453499; Orphanet: 453504; OMIM: 616580

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000747834	The Genetics Institute, Rambam Health Care Campus	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 1, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002572966	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002578985	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002605170	OMIM	no assertion criteria provided	Pathogenic (Nov 18, 2022)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	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	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

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Choufani S, McNiven V, Cytrynbaum C, Jangjoo M, Adam MP, Bjornsson HT, Harris J, Dyment DA, Graham GE, Nezarati MM, Aul RB, Castiglioni C, Breckpot J, Devriendt K, Stewart H, Banos-Pinero B, Mehta S, Sandford R, Dunn C, Mathevet R, van Maldergem L, Piard J, et al.

Am J Hum Genet. 2022 Oct 6;109(10):1867-1884. doi: 10.1016/j.ajhg.2022.08.014. Epub 2022 Sep 20.

PubMed [citation]

PMID:: 36130591
PMCID:: PMC9606382

Details of each submission

From The Genetics Institute, Rambam Health Care Campus, SCV000747834.1

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

Description

This sequence change replaces Glutamic acid with Lysine at codon 85 of the HNRNPK protein p.(Glu85Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (gmomAD, dbSNP,). This variant was found in an individual with clinical symptomes compatible with Au-Kline syndrome (MIM:616580 ), de novo inheritance was confirmed. ClinVar contains an entry for this variant (Variation ID: 452520). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55").

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

From 3billion, SCV002572966.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.29; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as likely pathogenic and uncertain significance for HNRNPK -related disorder (ClinVar ID: VCV000452520). Threrefore, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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

From MGZ Medical Genetics Center, SCV002578985.1

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

From OMIM, SCV002605170.1

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

Description

In 5 unrelated patients with Au-Kline syndrome (AUKS; 616580), Choufani et al. (2022) identified a de novo heterozygous c.253G-A transition (c.253G-A, NM_002140.4) in exon 6 of the HNRNPK gene, resulting in a glu85-to-lys (E85K) substitution. In 3 patients who were tested, an intermediate AUKS-specific DNA methylation signature was identified in patient blood.

#	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

Last Updated: Apr 15, 2024

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