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

dbSNP: rs587777148

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000515002	SCV000611060	pathogenic	not provided	2017-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000515002	SCV000709882	pathogenic	not provided	2022-05-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting in improper localization of the kaptin protein (Baple et al., 2014); In-frame insertion of 6 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 31999056, 24239382, 30008475, 32358097)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087080	SCV001208047	pathogenic	Macrocephaly-developmental delay syndrome	2022-05-04	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000515002	SCV001334672	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000515002	SCV002066295	likely pathogenic	not provided	2018-05-21	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000087080	SCV002577380	likely pathogenic	Macrocephaly-developmental delay syndrome	2022-06-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000087080	SCV002768939	pathogenic	Macrocephaly-developmental delay syndrome	2023-07-17	criteria provided, single submitter	clinical testing	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
Fulgent Genetics, Fulgent Genetics	RCV000087080	SCV002803419	pathogenic	Macrocephaly-developmental delay syndrome	2021-08-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003343637	SCV004058227	pathogenic	Inborn genetic diseases	2023-07-10	criteria provided, single submitter	clinical testing	The c.714_731dup18 (p.M241_Q246dup) alteration, located in coding exon 8 of the KPTN gene, results from an in-frame duplication of 18 nucleotides at_x000D_ positions 714 to 731. This results in the duplication of 6 amino acids from codons 241 to 246. Based on data from gnomAD, this allele has an overall frequency of 0.048% (135/279060) total alleles studied. The highest observed frequency was 0.101% (25/24646) of European (Finnish) alleles. This alteration was reported in trans with a second KPTN alteration in multiple individuals with features consistent with KPTN-related neurodevelopmental disorder (Baple, 2014; Thiffault, 2019; Thiffault, 2020). Functional analysis demonstrated that the p.M241_Q246dup alteration led to a mislocalized kaptin protein (Baple, 2014). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415870	SCV004114398	pathogenic	KPTN-related disorder	2023-03-14	criteria provided, single submitter	clinical testing	The KPTN c.714_731dup18 variant is predicted to result in an in-frame duplication (p.Met241_Gln246dup). This variant has been reported in the compound heterozygous state with a loss of function variant in KPTN (c.776C>A, p.Ser259*) in individuals with global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and features suggestive of a pervasive developmental disorder (Baple et al. 2014. PubMed ID: 24239382). This variant was also reported along with a splicing variant in KPTN (c.394+1G>A) in an individual with macrocephaly, intractable epilepsy, atrial septal defect, global developmental delay, hypotonia, hypoglycemia, and dysmorphia (Phase not reported, Thiffault et al. 2018. PubMed ID: 30008475). This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-47983175-G-GACCGACCACATCTGCAGA). This variant is interpreted as pathogenic.
OMIM	RCV000087080	SCV000119894	pathogenic	Macrocephaly-developmental delay syndrome	2014-01-02	no assertion criteria provided	literature only