19-11120488-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6
The NM_000527.5(LDLR):c.2106G>A(p.Met702Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000644 in 1,613,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.2106G>A | p.Met702Ile | missense_variant | 14/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.2106G>A | p.Met702Ile | missense_variant | 14/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152204Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000124 AC: 31AN: 250972Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135712
GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461472Hom.: 0 Cov.: 35 AF XY: 0.0000646 AC XY: 47AN XY: 727046
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152204Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74358
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 21, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with high LDL-C levels and/or FH in the published literature (Lange et al., 2014; Wintjens et al., 2016; Dron et al., 2020); This variant is associated with the following publications: (PMID: 26802169, 25487149, 30487145, 24507775, 32041611) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 25, 2019 | - - |
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain: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. - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | subject mutated among 2600 FH index cases screened = 1/Software predictions: Conflicting - |
Familial hypercholesterolemia Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 23, 2020 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 14, 2023 | Variant summary: LDLR c.2106G>A (p.Met702Ile) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250972 control chromosomes (gnomAD), predominantly at a frequency of 0.0026 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.2106G>A has been reported in the literature in individuals affected with Hypercholesterolemia (Lange_2014, Wintjens_2016), Dyslipidemia (Dron_2020), and in an individual with Myocardial Infarction (Do_2015) without evidence for causality. The variant was also reported in control individuals (Do_2015, Rego_2018). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25487149, 32041611, 24507775, 30487145, 26802169). Seven ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at