Submissions for variant NM_003383.5(VLDLR):c.1643A>G (p.Lys548Arg)

gnomAD frequency: 0.00053  dbSNP: rs148487944

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118818	SCV000153465	uncertain significance	not specified	2018-06-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000298244	SCV000479351	uncertain significance	Congenital cerebellar hypoplasia	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000767000	SCV000565657	likely benign	not provided	2019-11-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000767000	SCV001155597	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001168020	SCV001330573	uncertain significance	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1	2018-01-12	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000767000	SCV001713480	uncertain significance	not provided	2020-07-16	criteria provided, single submitter	clinical testing
Invitae	RCV000767000	SCV003284326	uncertain significance	not provided	2022-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 548 of the VLDLR protein (p.Lys548Arg). This variant is present in population databases (rs148487944, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with VLDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 130704). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.