Submissions for variant NM_001220.5(CAMK2B):c.416C>T (p.Pro139Leu)

dbSNP: rs1554389088

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623203	SCV000742890	pathogenic	Inborn genetic diseases	2017-10-12	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000516163	SCV000746610	pathogenic	Intellectual disability, autosomal dominant 54	2017-09-11	criteria provided, single submitter	clinical testing	This variant has been reported in PMID:29100089 (individual 20).
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814167	SCV001755627	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001571738	SCV001796261	pathogenic	not provided	2021-10-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (impairment of neuronal migration in murine models) (Kury et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 29100089, 30842224, 29100083, 30577886, 31036916, 30979967, 32875707, 31785789)
3billion	RCV000516163	SCV002058965	pathogenic	Intellectual disability, autosomal dominant 54	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in at least two similarly affected unrelated individuals (PMID: 29100089, PS4_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Mental retardation (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29100089, , PS2_S). . Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA	RCV000516163	SCV002097279	pathogenic	Intellectual disability, autosomal dominant 54	2022-02-14	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29100089) - PS3_moderate. The c.416C>T;p.(Pro139Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 430922; PMID: 32875707; 29100089) - PS4. This variant is not present in population databases (rs1554389088, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32875707; 29100089) - PM6. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001571738	SCV002206002	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 430922). This missense change has been observed in individual(s) with CAMK2B-related conditions (PMID: 29100089, 30842224, 31036916). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 139 of the CAMK2B protein (p.Pro139Leu). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAMK2B function (PMID: 29100089).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000516163	SCV002576438	pathogenic	Intellectual disability, autosomal dominant 54	2024-01-22	criteria provided, single submitter	clinical testing	Criteria applied: PS4, PS2_VSTR, PS3_MOD, PM2_SUP, PP2
Neuberg Centre For Genomic Medicine, NCGM	RCV000516163	SCV002820184	likely pathogenic	Intellectual disability, autosomal dominant 54		criteria provided, single submitter	clinical testing	The missense variant p.P139L in CAMK2B (NM_001220.4) hasbeen previously reported in an affected patient (Kury et al,2017). It has been classified as Likely Pathogenic in the ClinVar database. The p.P139L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P139L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 139 of CAMK2B is conserved in all mammalian species. The nucleotide c.416 in CAMK2B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000516163	SCV004045894	pathogenic	Intellectual disability, autosomal dominant 54	2023-02-21	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000577890	SCV000583489	pathogenic	Intellectual disability	2017-07-03	no assertion criteria provided	research
OMIM	RCV000516163	SCV000612158	pathogenic	Intellectual disability, autosomal dominant 54	2022-04-28	no assertion criteria provided	literature only
Gene Discovery Core-Manton Center, Boston Children's Hospital	RCV000516163	SCV000930676	likely pathogenic	Intellectual disability, autosomal dominant 54	2019-02-05	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003964	SCV001161973	likely pathogenic	Dystonic disorder; Global developmental delay; Apnea; Hyperventilation; Microcephaly; Agitation		no assertion criteria provided	research