Submissions for variant NM_004218.4(RAB11B):c.64G>A (p.Val22Met)

dbSNP: rs1555690779

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
SIB Swiss Institute of Bioinformatics	RCV000523787	SCV000883217	likely pathogenic	Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter. The following ACMG Tag(s) were applied: PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29106825). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP2 => Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (https://www.ncbi.nlm.nih.gov/pubmed/29106825). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29106825).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000523787	SCV002769088	pathogenic	Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter	2022-02-02	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: 0105 - The mechanism of disease for this gene is not clearly established (PMID: 29106825). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as a de novo event in multiple individuals with RAB11B -related neurodevelopmental disorder (DECIPHER, PMID: 29106825). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis of transfected TERT cells showed a significant change in intracellular localization and binding affinity to interacting proteins (PMID: 29106825). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000523787	SCV000622108	pathogenic	Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter	2017-12-15	no assertion criteria provided	literature only
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000523787	SCV002073942	pathogenic	Neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter	2022-02-08	no assertion criteria provided	clinical testing