rs35339834
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_003383.5(VLDLR):c.1901G>A(p.Arg634His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,170 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R634C) has been classified as Uncertain significance.
Frequency
Consequence
NM_003383.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VLDLR | NM_003383.5 | c.1901G>A | p.Arg634His | missense_variant | 13/19 | ENST00000382100.8 | |
VLDLR | NM_001018056.3 | c.1901G>A | p.Arg634His | missense_variant | 13/18 | ||
VLDLR | NM_001322225.2 | c.1778G>A | p.Arg593His | missense_variant | 12/18 | ||
VLDLR | NM_001322226.2 | c.1778G>A | p.Arg593His | missense_variant | 12/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VLDLR | ENST00000382100.8 | c.1901G>A | p.Arg634His | missense_variant | 13/19 | 1 | NM_003383.5 |
Frequencies
GnomAD3 genomes ? AF: 0.000979 AC: 149AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000769 AC: 193AN: 251122Hom.: 0 AF XY: 0.000685 AC XY: 93AN XY: 135698
GnomAD4 exome AF: 0.00169 AC: 2477AN: 1461856Hom.: 2 Cov.: 32 AF XY: 0.00167 AC XY: 1216AN XY: 727228
GnomAD4 genome ? AF: 0.000978 AC: 149AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70AN XY: 74488
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 23, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 29117201) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 15, 2022 | 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. - |
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 06, 2015 | - - |
Congenital cerebellar hypoplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
VLDLR-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 19, 2022 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at