rs774698247
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_000527.5(LDLR):c.2289G>T(p.Glu763Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,096 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Likely benign (★★).
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.2289G>T | p.Glu763Asp | missense_variant | 15/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.2289G>T | p.Glu763Asp | missense_variant | 15/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000267 AC: 67AN: 251144Hom.: 3 AF XY: 0.000353 AC XY: 48AN XY: 135816
GnomAD4 exome AF: 0.000133 AC: 195AN: 1461844Hom.: 5 Cov.: 34 AF XY: 0.000194 AC XY: 141AN XY: 727220
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74438
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Apr 13, 2010 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Likely benign, criteria provided, single submitter | literature only;research | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Familial hypercholesterolemia Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 23, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 31, 2020 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 27, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 30, 2018 | See Variant Classification Assertion Criteria. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 04, 2017 | The p.Glu763Asp variant in LDLR has been reported in 2 individuals with hypercholesterolemia (Hooper 2012, Bangash 2014). This variant has been identified in 0.21% (66/30782) of South Asian chromosomes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs774698247) and is reported in ClinVar (Variation ID: 226389). Computational prediction tools and conservation analysis suggest that the p.Glu763Asp variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the p.Glu763Asp variant is likely benign due to its frequency in the general population. ACMG/AMP Criteria applied: PS4_Supporting, BP4, BS1. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at