19-11102741-G-T
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM5_StrongPM2PP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755).The supporting evidence is as follows: PM5_Strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PM5 - Four more missense variants described in same codon, 3 variants classified as Pathogenic, so PM5 is Met.PP3 - REVEL = 0.958. It is above 0.75, so PP3 is Met.PP4 - Variant meets PM2. Identified in 1 index case who fulfills Simon-Broome criteria from Center of molecular biology and gene therapy. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584820/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, familial, 1Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | MANE Select | c.268G>T | p.Asp90Tyr | missense | Exon 3 of 18 | NP_000518.1 | ||
| LDLR | NM_001195798.2 | c.268G>T | p.Asp90Tyr | missense | Exon 3 of 18 | NP_001182727.1 | |||
| LDLR | NM_001195800.2 | c.268G>T | p.Asp90Tyr | missense | Exon 3 of 16 | NP_001182729.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | TSL:1 MANE Select | c.268G>T | p.Asp90Tyr | missense | Exon 3 of 18 | ENSP00000454071.1 | ||
| LDLR | ENST00000252444.10 | TSL:1 | c.526G>T | p.Asp176Tyr | missense | Exon 3 of 18 | ENSP00000252444.6 | ||
| LDLR | ENST00000558013.5 | TSL:1 | c.268G>T | p.Asp90Tyr | missense | Exon 3 of 18 | ENSP00000453346.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5
The NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM5_Strong - Four more missense variants described in same codon: --- 3 variants classified as Pathogenic, so PM5_Strong is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PM5 - Four more missense variants described in same codon, 3 variants classified as Pathogenic, so PM5 is Met. PP3 - REVEL = 0.958. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2. Identified in 1 index case who fulfills Simon-Broome criteria from Center of molecular biology and gene therapy.
This missense variant (also known as p.Asp69Tyr in the mature protein) replaces aspartic acid with tyrosine at codon 90 in the second LDLR type A of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 34456200). This variant has also been reported in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 8347689). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon (p.Asp90Asn, p.Asp90Gly, p.Asp90Glu, p.Asp90Ala), are well documented pathogenic mutations (ClinVar variation IDs: 215505, 226313, 251107, 440555), indicating that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
The missense c.268G>T p.Asp90Tyr variant in the LDLR gene has been observed in individuals with familial hypercholesterolemia Rubinsztein, D C et al., 1993. Other variants that disrupt this residue have been determined to be pathogenic Han, Soo Min et al., 2015. The variant is absent in gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic reviewed by expert panel. The amino acid Aspartic acid at position 90 is changed to a Tyrosine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid Aspartic acid in LDLR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Cardiovascular phenotype Pathogenic:1
The p.D90Y pathogenic mutation (also known as c.268G>T), located in coding exon 3 of the LDLR gene, results from a G to T substitution at nucleotide position 268. The aspartic acid at codon 90 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, which is also known as p.D69Y, has been reported in individuals with concerns for familial hypercholesterolemia (FH), including being identified in trans with another alteration in LDLR in an individual with homozygous FH (Rubinsztein DC et al. Biochim Biophys Acta, 1993 Aug;1182:75-82; Kim H et al. J Atheroscler Thromb, 2022 Aug;29:1176-1187; Ambry internal data). Another variant at the same codon, p.D90N (c.268G>A), has been detected in multiple individuals with FH and in FH cohorts from a variety of ethnic backgrounds (Day IN et al. Hum. Mutat., 1997;10:116-27; Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Khoo KL et al. Clin. Genet., 2000 Aug;58:98-105; Chang JH et al. J. Lipid Res., 2003 Oct;44:1850-8; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Norsworthy PJ et al. BMC Med. Genet., 2014 Jun;15:70). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Familial hypercholesterolemia Pathogenic:1
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 90 of the LDLR protein (p.Asp90Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 8347689). This variant is also known as FH Durban-1 and asp69tyr. ClinVar contains an entry for this variant (Variation ID: 251106). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Asp90 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12837857, 16343504, 21376320, 25962062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at