rs35948251
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_003383.5(VLDLR):c.1838G>A(p.Arg613His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R613R) has been classified as Likely benign.
Frequency
Consequence
NM_003383.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VLDLR | NM_003383.5 | c.1838G>A | p.Arg613His | missense_variant | 13/19 | ENST00000382100.8 | |
VLDLR | NM_001018056.3 | c.1838G>A | p.Arg613His | missense_variant | 13/18 | ||
VLDLR | NM_001322225.2 | c.1715G>A | p.Arg572His | missense_variant | 12/18 | ||
VLDLR | NM_001322226.2 | c.1715G>A | p.Arg572His | missense_variant | 12/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VLDLR | ENST00000382100.8 | c.1838G>A | p.Arg613His | missense_variant | 13/19 | 1 | NM_003383.5 |
Frequencies
GnomAD3 genomes ? AF: 0.000177 AC: 27AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251196Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135762
GnomAD4 exome AF: 0.000238 AC: 348AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.000220 AC XY: 160AN XY: 727218
GnomAD4 genome ? AF: 0.000177 AC: 27AN: 152298Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74472
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 07, 2015 | - - |
Congenital cerebellar hypoplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2018 | 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. - |
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Uncertain:1
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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at