rs879255079
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3PM2PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PS3 - 2 Level 1 assays: PMID 25386756:Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake.PMID 23021490:Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein.---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PP4 - Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585687/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1942T>C | p.Ser648Pro | missense_variant | 13/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1942T>C | p.Ser648Pro | missense_variant | 13/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/200 non-FH alleles - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | The NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - 2 Level 1 assays: PMID 25386756: Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake. PMID 23021490: Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein. ---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP4 - Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2022 | Published functional studies demonstrate a damaging effect as expression in transfected cell lines is significantly reduced (Etxebarria A et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as S627P using alternate nomenclature in an individual with familial hypercholesterolemia (Bourbon M et al., 2008); This variant is associated with the following publications: (PMID: 23021490, 25386756, 17765246) - |
Familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 22, 2023 | Variant summary: LDLR c.1942T>C (p.Ser648Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251468 control chromosomes (gnomAD). c.1942T>C has been reported in the literature in at least one individual affected with Hypercholesterolemia (Bourbon_2008). At least two publications reports experimental evidence evaluating an impact on protein function, finding substantially decreased mature LDLR protein and impaired uptake and degredation of LDL (Silva_2012, Etxebarria_2014). The following publications have been ascertained in the context of this evaluation (PMID: 17765246, 23021490, 25386756). Three submitters have provided 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 likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at