ClinVar Miner

Submissions for variant NM_015443.4(KANSL1):c.808_809del (p.Leu270fs)

gnomAD frequency: 0.00001  dbSNP: rs551541795
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001093449 SCV001250442 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001266716 SCV001444893 pathogenic Inborn genetic diseases 2023-04-28 criteria provided, single submitter clinical testing The c.808_809delCT (p.L270Vfs*11) alteration, located in exon 2 (coding exon 1) of the KANSL1 gene, consists of a deletion of 2 nucleotides from position 808 to 809, causing a translational frameshift with a predicted alternate stop codon after 11 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.808_809delCT allele has an overall frequency of 0.002% (7/282852) total alleles studied. The highest observed frequency was 0.01% (3/30616) of South Asian alleles. Loss of function alterations in this region of the KANSL1 gene are more common in population databases than expected for likely pathogenic/disease-causing variants (Koolen, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics RCV000551044 SCV001529643 pathogenic Koolen-de Vries syndrome 2018-09-28 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity RCV000551044 SCV002016761 likely pathogenic Koolen-de Vries syndrome 2022-05-26 criteria provided, single submitter clinical testing
Breda Genetics srl RCV000551044 SCV002586269 likely pathogenic Koolen-de Vries syndrome 2022-06-23 criteria provided, single submitter clinical testing The variant c.808_809del (p.Leu270Valfs*11) in the KANSL1 gene is reported with conflicting interpretations (pathogenic, likely pathogenic, uncertain) in ClinVar for Koolen-de Vries syndrome (Variation ID: 168412) and as likely pathogenic in the LOVD database v.3.0 (genomic variant: #0000795640). The variant c.808_809del (p.Leu270Valfs*11) has been reported as pathogenic by Niar et al. (2018, PMID: 30293248) in a patient with a diagnosis of Koolen-deVries syndrome, which had developmental delay, intellectual disability, hypotony, ptosis, short stature, and ligamentous laxity. The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 11 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.00002386 in gnomAD exomes and di 0.00003185 in gnomAD genomes with no homozygous individuals reported.
PreventionGenetics, part of Exact Sciences RCV003403305 SCV004105304 pathogenic KANSL1-related disorder 2023-04-25 criteria provided, single submitter clinical testing The KANSL1 c.808_809delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu270Valfs*11). This variant was reported in multiple individuals with Koolen-de Vries syndrome or a neurodevelopmental phenotype. In many cases, the variant arose de novo (Nair et al. 2018. PubMed ID: 30293248; Table S1 - Gabriel et al. 2021. PubMed ID: 34958143; Tolusso et al. 2021. PubMed ID: 33442022; Table S2 - Turner et al. 2019. PubMed ID: 31785789). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-44248700-CAG-C). Frameshift variants in KANSL1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000551044 SCV005644150 uncertain significance Koolen-de Vries syndrome 2024-04-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000551044 SCV000645070 uncertain significance Koolen-de Vries syndrome 2021-08-31 flagged submission clinical testing
Mendelics RCV002248770 SCV002517223 uncertain significance not specified 2022-05-04 flagged submission clinical testing

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