Submissions for variant NM_003718.5(CDK13):c.484dup (p.Ala162fs)

dbSNP: rs1405252481

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598864	SCV000710325	likely pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 30525188, 29393965, 33879837, 31238879)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000786912	SCV001369345	uncertain significance	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2019-08-09	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2.
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV000786912	SCV002577731	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2022-10-04	criteria provided, single submitter	clinical testing	PVS1;PS4;PM2_supporting;PM6
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000786912	SCV002769283	uncertain significance	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Both dominant negative and haploinsufficiency have been suggested, although not proven with functional studies (PMID: 29393965, PMID: 30904094). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). However, this variant does not pass gnomAD data quality filters. (I) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Other NMD-predicted variants have been reported as pathogenic in ClinVar, and also in individuals with neurodevelopmental disorders in the literature (PMID: 29393965, 31238879). (SP) 0801 - This variant has previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in 3 unrelated patients with developmental delay, 2 of which were shown to be de novo (PMID: 29393965). This variant has also been reported in ClinVar both as pathogenic and as a VUS. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Illumina Laboratory Services, Illumina	RCV000786912	SCV004014724	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2023-04-07	criteria provided, single submitter	clinical testing	The CDK13 c.484dup (p.Ala162GlyfsTer108) variant is a duplication of a nucleotide at position c.484, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in at least four individuals with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder; in three of these cases, the variant was confirmed to have a de novo occurrence (PMID: 29393965; PMID: 30525188). The p.Ala162GlyfsTer108 variant is reported in the Genome Aggregation Database in four alleles at a frequency of 0.000026 in the Total population (version 3.1.2), however, these variants failed allele-specific VQSR filter, so this frequency data may be unreliable. This variant was identified in a de novo state. Based on the available evidence, the c.484dup (p.Ala162GlyfsTer108) variant is classified as pathogenic for congenital heart defects, dysmorphic facial features, and intellectual developmental disorder.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000786912	SCV004032315	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2023-08-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS2_VSTR,PS4_MOD,PM2_SUP
Baylor Genetics	RCV000786912	SCV004041411	likely pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2023-05-23	criteria provided, single submitter	clinical testing
Invitae	RCV000598864	SCV004311164	pathogenic	not provided	2023-07-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 504021). This premature translational stop signal has been observed in individual(s) with syndromic intellectual disability (PMID: 29393965). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ala162Glyfs*108) in the CDK13 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDK13 are known to be pathogenic (PMID: 27479907, 29021403, 29393965).
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786912	SCV000925813	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2018-12-12	no assertion criteria provided	clinical testing
MedGen Diagnostic Laboratory, MedGen Medical Centre	RCV000786912	SCV002558802	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2022-08-08	no assertion criteria provided	clinical testing	The variant is de novo. In patient we observed: short stature, dysmorphic features, intellectual disability. In summary, this variant meets criteria to be classified as pathogenic.