Submissions for variant NM_001007527.2(LMBRD2):c.1448G>A (p.Arg483His)

dbSNP: rs2111857835

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion, Medical Genetics	RCV001810513	SCV002521135	likely pathogenic	Developmental delay with variable neurologic and brain abnormalities	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.69). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 32820033). A different missense change at the same codon (p.Arg483Cys) has been reported to be associated with LMBRD2 related disorder (ClinVar ID: VCV000982396). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001810513	SCV002558892	pathogenic	Developmental delay with variable neurologic and brain abnormalities		criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV002276901	SCV002564479	likely pathogenic	Neurodevelopmental disorder	2021-11-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf	RCV001810513	SCV004013438	likely pathogenic	Developmental delay with variable neurologic and brain abnormalities	2025-01-22	criteria provided, single submitter	not provided	PS4_Mod, PM5, PM6 (de novo in our patient), PM2_Sup, PP3
GeneDx	RCV003318692	SCV004022717	pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32820033)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001810513	SCV004099670	pathogenic	Developmental delay with variable neurologic and brain abnormalities	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: LMBRD2 c.1448G>A (p.Arg483His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246142 control chromosomes (gnomAD). c.1448G>A has been reported in the literature occuring de novo in three individuals affected with Developmental Delay With Variable Neurologic And Brain Abnormalities (Malhotra_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32820033). Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004536326	SCV004116756	pathogenic	LMBRD2-related disorder	2022-09-15	criteria provided, single submitter	clinical testing	The LMBRD2 c.1448G>A variant is predicted to result in the amino acid substitution p.Arg483His. This variant was reported as being de novo in multiple individuals with developmental/motor delays, structural brain anomalies, and dysmorphic features (Malhotra et al. 2021. PubMed ID: 32820033). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001810513	SCV005395963	likely pathogenic	Developmental delay with variable neurologic and brain abnormalities	2024-11-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004797953	SCV005419298	likely pathogenic	See cases	2024-11-05	criteria provided, single submitter	clinical testing	ACMG categories: PS4,PM2,PM5,PP3
OMIM	RCV001810513	SCV002059954	pathogenic	Developmental delay with variable neurologic and brain abnormalities	2023-04-10	no assertion criteria provided	literature only