rs139877665
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_015627.3(LDLRAP1):c.284G>A(p.Arg95Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000652 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 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. R95W) has been classified as Uncertain significance.
Frequency
Consequence
NM_015627.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLRAP1 | NM_015627.3 | c.284G>A | p.Arg95Gln | missense_variant | 3/9 | ENST00000374338.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLRAP1 | ENST00000374338.5 | c.284G>A | p.Arg95Gln | missense_variant | 3/9 | 1 | NM_015627.3 | P1 | |
LDLRAP1 | ENST00000462394.1 | n.32G>A | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
LDLRAP1 | ENST00000488127.1 | n.754G>A | non_coding_transcript_exon_variant | 2/7 | 2 | ||||
LDLRAP1 | ENST00000485476.2 | downstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000558 AC: 85AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000760 AC: 191AN: 251378Hom.: 0 AF XY: 0.000817 AC XY: 111AN XY: 135872
GnomAD4 exome AF: 0.000662 AC: 968AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.000648 AC XY: 471AN XY: 727234
GnomAD4 genome ? AF: 0.000558 AC: 85AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.000713 AC XY: 53AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 17, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2018 | A variant of uncertain significance has been identified in the LDLRAP1 gene. The R95Q variant has not been published as pathogenic or been reported as benign to our knowledge. The R95Q variant is observed in 67/25,790 (0.26%) alleles from individuals of European (Finnish) ancestry and in 124/126,650 (0.1%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts, though no individuals were reported to be homozygous (Lek et al., 2016). The R95Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. - |
Hypercholesterolemia, familial, 4 Uncertain:1Benign: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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2023 | Variant summary: LDLRAP1 c.284G>A (p.Arg95Gln) results in a conservative amino acid change located in the phosphotyrosine binding (PTB) domain (IPR006020) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 251378 control chromosomes, predominantly in the Swedish and Finnish subpopulations, with a frequency of 0.0021 and 0.0026, respectively; although no homozygotes were reported. c.284G>A has been reported in the literature in heterozygous state as a VUS in the settings of multigene panel testing for dyslipidemia and metabolic disorders (Dron_2020), and in an index subject with definite or probable FH (Raal_2020), however, in this latter case it co-occurred with a pathogenic variant in the LDLR gene (c.2043C>A (p.Cys681Ter)). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=4) and Likely Benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at