Submissions for variant NM_003383.5(VLDLR):c.1838G>A (p.Arg613His)

gnomAD frequency: 0.00017  dbSNP: rs35948251

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193084	SCV000249380	uncertain significance	not specified	2015-01-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000359068	SCV000479355	uncertain significance	Congenital cerebellar hypoplasia	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000658403	SCV000780175	uncertain significance	not provided	2018-05-30	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the VLDLR gene. The R613H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 28/126434 (0.02%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The R613H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV001168790	SCV001331411	uncertain significance	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.