Submissions for variant NM_003383.5(VLDLR):c.1901G>A (p.Arg634His)

gnomAD frequency: 0.00108  dbSNP: rs35339834

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723635	SCV000225840	uncertain significance	not provided	2015-01-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000194482	SCV000249381	uncertain significance	not specified	2015-02-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000270534	SCV000479356	uncertain significance	Congenital cerebellar hypoplasia	2016-06-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764831	SCV000895987	uncertain significance	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000764831	SCV001331412	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.
GeneDx	RCV000723635	SCV001795514	uncertain significance	not provided	2024-10-15	criteria provided, single submitter	clinical testing	Reported previously in the compound heterozygous state in a patient with autism spectrum disorder; however, no further clinical information was provided and the patient also harbored a variant in a different gene (PMID: 35668055); 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: 29117201, 35668055)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000723635	SCV002305237	uncertain significance	not provided	2022-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 634 of the VLDLR protein (p.Arg634His). This variant is present in population databases (rs35339834, gnomAD 0.2%), 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: 194212). 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: "Probably 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.
PreventionGenetics, part of Exact Sciences	RCV003917617	SCV004736580	likely benign	VLDLR-related disorder	2022-04-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).