19-11111550-A-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000527.5(LDLR):āc.1097A>Gā(p.Gln366Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Q366P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1097A>G | p.Gln366Arg | missense_variant | Exon 8 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251362Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461614Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727128
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Familial hypercholesterolemia Pathogenic:2
Variant summary: LDLR c.1097A>G (p.Gln366Arg) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251762 control chromosomes, predominantly at a frequency of 4.4e-05 within the Non-Finnish European subpopulation in the gnomAD database. c.1097A>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Gunderson_1996, Lind_2002, Leren_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 366 of the LDLR protein (p.Gln366Arg). This variant is present in population databases (rs746982741, gnomAD 0.004%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 8931648, 9104431, 12052488). This variant is also known as Q345R. ClinVar contains an entry for this variant (Variation ID: 251662). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Hyperlipidemia Pathogenic:1
Observed in a heterozygous state, at our lab, in a patient with matching phenotype. ACMG criteria used (according to ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2): PS4, PM2, PM5, PP3 and PP4. -
Hypercholesterolemia, familial, 1 Pathogenic:1
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not provided Uncertain:1
Has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 12052488, 9104431, 33955087); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Q345R); This variant is associated with the following publications: (PMID: 10090473, 15523646, 18700895, 21310417, 8740918, 15199436, 33740630, 12052488, 33955087, 9104431, 8931648) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at