19-11110720-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000527.5(LDLR):c.1009G>A(p.Glu337Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E337G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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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.1009G>A | p.Glu337Lys | missense_variant | 7/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1009G>A | p.Glu337Lys | missense_variant | 7/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000104 AC: 26AN: 251000Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135808
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461568Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727078
GnomAD4 genome AF: 0.000184 AC: 28AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74452
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 28, 2021 | - - |
Uncertain significance, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 07, 2023 | This missense variant (also known as p.Glu316Lys in the mature protein) replaces glutamic acid with lysine at codon 337 of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 28964736, 29353225, 29396260; Shakhtshneider et al., 2017). This variant has also been identified in 30/282380 chromosomes (19/30612 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Familial hypercholesterolemia Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 04, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 29, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 337 of the LDLR protein (p.Glu337Lys). This variant is present in population databases (rs539080792, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 29353225, 29396260). ClinVar contains an entry for this variant (Variation ID: 523729). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 15, 2023 | This missense variant (also known as p.Glu316Lys in the mature protein) replaces glutamic acid with lysine at codon 337 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 28964736, 29353225, 29396260, 34834584; Color internal data). This variant has also been identified in 30/282380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28964736, 33418990, 34834584, 29396260, 29353225) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 27, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 27, 2022 | 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