NM_007059.4(KPTN):c.714_731dup (p.Gln246_Asp247insMetTrpSerValLeuGln) AND Macrocephaly-developmental delay syndrome

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 17, 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:: RCV000087080.22

Allele description [Variation Report for NM_007059.4(KPTN):c.714_731dup (p.Gln246_Asp247insMetTrpSerValLeuGln)]

NM_007059.4(KPTN):c.714_731dup (p.Gln246_Asp247insMetTrpSerValLeuGln)

Gene:

KPTN:kaptin, actin binding protein [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

19q13.32

Genomic location:

Preferred name:

NM_007059.4(KPTN):c.714_731dup (p.Gln246_Asp247insMetTrpSerValLeuGln)

HGVS:

NC_000019.10:g.47479922_47479939dup
NG_034097.1:g.9329_9346dup
NM_001291296.2:c.546_563dup
NM_007059.4:c.714_731dupMANE SELECT
NP_001278225.1:p.Gln190_Asp191insMetTrpSerValLeuGln
NP_008990.2:p.Gln246_Asp247insMetTrpSerValLeuGln
NC_000019.9:g.47983175_47983176insACCGACCACATCTGCAGA
NC_000019.9:g.47983179_47983196dup
NM_007059.2:c.714_731dupTCTGCAGATGTGGTCGGT
NM_007059.3:c.714_731dup
NR_111923.2:n.860_877dup

Links:

OMIM: 615620.0002; dbSNP: rs587777148

NCBI 1000 Genomes Browser:

rs587777148

Molecular consequence:

NM_001291296.2:c.546_563dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_007059.4:c.714_731dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NR_111923.2:n.860_877dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Macrocephaly-developmental delay syndrome (MRT41)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 41
Identifiers:: MONDO: MONDO:0014289; MedGen: C3810225; Orphanet: 397612; OMIM: 615637

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000119894	OMIM	no assertion criteria provided	Pathogenic (Jan 2, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 24239382, 32358097
SCV001208047	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 4, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24239382, 28492532
SCV002577380	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002768939	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24239382, 32358097, 25741868
SCV002803419	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 25, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005397445	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32358097, 24239382, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing.

Thiffault I, Atherton A, Heese BA, T Abdelmoity A, Pawar K, Farrow E, Zellmer L, Miller N, Soden S, Saunders C.

Cold Spring Harb Mol Case Stud. 2020 Jun 12;6(3). doi: 10.1101/mcs.a003970. Print 2020 Jun.

PubMed [citation]

PMID:: 32358097
PMCID:: PMC7304362

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000119894.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

For discussion of the 18-bp in-frame duplication in exon 8 of the KPTN gene (c.714_731dup) that was found in compound heterozygous state in patients with autosomal recessive intellectual developmental disorder-41 (MRT41; 615637) by Baple et al. (2014), see 615620.0001.

In a 9-year-old boy with MRT41, Thiffault et al. (2020) identified compound heterozygous mutations in the KPTN gene, c.714_731dup (c.714_731dup, NM_007059.2) and a c.394+1G-A transition (615620.0004) in intron 3, predicted to result in a splicing abnormality. The mutations were identified by whole-genome sequencing and confirmed by Sanger sequencing. The mother was shown to be a carrier of the splice site variant but not the duplication, indicating that the variants were in trans. The c.714_731dup variant was present in the gnomAD database at an allele frequency of 0.05%, and the c.394+1G-A variant was present in the gnomAD database at an allele frequency of 0.007%. Functional studies were not performed.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001208047.3

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

Description

This variant, c.714_731dup, results in the insertion of 6 amino acid(s) of the KPTN protein (p.Met241_Gln246dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763764442, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with macrocephaly, neurodevelopmental delay and seizures (PMID: 24239382). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 100680). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects KPTN function (PMID: 24239382). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

From Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn, SCV002577380.1

#	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768939.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual disability 41 (MIM#615637). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0216 - In-frame insertion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 135 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable in frame duplication variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least six compound heterozygous probands with a neurodevelopmental disorder, including multiple affecteds in a large Amish family. In addition, it has been consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID:24239382, 32358097). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays have demonstrated protein mislocalization (PMID: 24239382). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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, SCV002803419.1

#	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

From Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center, SCV005397445.1

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

Description

This sequence variant is an eighteen nucleotide duplication (dupACCGACCACATCTGCAGA) that results in the inframe insertion of 6 amino acids in exon 8 of 12 of the KPTN gene. This previously reported variant (ClinVar) has been observed in individuals affected by macrocephaly, neurodevelopmental delay and seizures when in the compound heterozygous state (PMID: 32358097). In addition, this variant, when in the compound heterozygous state, co-segregates with this disorder across multiple Ohio Amish families (PMID: 24239382). This variant is rare in control population datasets (gnomAD database, 135 of 279,060 alleles, 0.05%). Routine bioinformatic tools cannot predict the impact this variant will have on the function of kaptin, KPTN's encoded protein. However, protein folding models suggest that this duplication will disrupt the tertiary structure of kaptin (PMID: 24239382), and a functiol study indicates that the protein created by this variant fails to properly localize in neurons (PMID: 24239382). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM3, PM4, PP1, PS3

#	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

Last Updated: Nov 18, 2024

ClinVar

Relating variation to medicine