rs730882102
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP5BP4
The NM_000527.5(LDLR):c.1414G>A(p.Asp472Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. D472Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1414G>A | p.Asp472Asn | missense_variant | 10/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1414G>A | p.Asp472Asn | missense_variant | 10/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461740Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12AN XY: 727182
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 03, 2021 | Variant summary: LDLR c.1414G>A (p.Asp472Asn) results in a conservative amino acid change located in the LDLR class B repeat domain (IPR000033; InterPro) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251206 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1414G>A has been reported in the literature in an individual affected with hypercholesterolemia, and the authors of this study classified the variant as likely pathogenic, however no information was provided for independent evaluation (Marmontel_2018). Therefore, these data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different missense affecting the same residue, c.1414G>T (p.Asp472Tyr), is classified as likely pathogenic by our laboratory. In addition, missense changes affecting nearby residues (e.g. Y465C, T467I, S470C, I473N, A475V) have been reported in individuals affected with hypercholesterolaemia (HGMD), suggesting that this protein region may be clinically significant. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at