19-11113376-G-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4PP3PS4_SupportingPM5PS3PM2
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1285G>C (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PM5, PP3, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.764. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G=6 from PathWest Laboratory Medicine WA, Australia; 1 case with possible FH by Simon Broome criteria from Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal, PMID 17765246 (Bourbon et al., 2008). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576303/MONDO:0007750/013
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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1285G>C | p.Val429Leu | missense_variant | 9/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3Uncertain:1
Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Mar 27, 2023 | The NM_000527.5(LDLR):c.1285G>C (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PM5, PP3, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.764. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G<A (p.Val429Met) (ClinVar ID: 3694). PS3: Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 22% cell surface LDLR and binding and 10% uptake, PMID 25386756 (Etxebarria et al., 2014). Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 15-30% LDLR activity, reduced mature protein, PMID 23021490 (Silva et al, 2012). ---- Overall, functional studies show an activity below 70% of wild-type, consistent with damaging effect. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases (2 cases with DLCN score >=6 from PathWest Laboratory Medicine WA, Australia; 1 case with possible FH by Simon Broome criteria from Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal, PMID 17765246 (Bourbon et al., 2008). - |
Uncertain significance, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Oct 04, 2013 | - - |
Pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/208 non-FH alleles - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at