chr19-11106630-C-T
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM3PVS1PM2PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PM3 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: PVS1 - Variant leads to stop at codon 254. It is amino-terminal of amino acid 830, so PVS1 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM3 - variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID:28028493).-- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met.PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID:28028493), China, so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585116/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 stop_gained
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: Pathogenic. The variant received 13 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.760C>T | p.Gln254* | stop_gained | Exon 5 of 18 | NP_000518.1 | ||
| LDLR | NM_001195798.2 | c.760C>T | p.Gln254* | stop_gained | Exon 5 of 18 | NP_001182727.1 | |||
| LDLR | NM_001195799.2 | c.637C>T | p.Gln213* | stop_gained | Exon 4 of 17 | NP_001182728.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | TSL:1 MANE Select | c.760C>T | p.Gln254* | stop_gained | Exon 5 of 18 | ENSP00000454071.1 | ||
| LDLR | ENST00000252444.10 | TSL:1 | c.1018C>T | p.Gln340* | stop_gained | Exon 5 of 18 | ENSP00000252444.6 | ||
| LDLR | ENST00000558013.5 | TSL:1 | c.760C>T | p.Gln254* | stop_gained | Exon 5 of 18 | ENSP00000453346.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
The NM_000527.5(LDLR):c.760C>T (p.Gln254Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PM3 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: PVS1 - Variant leads to stop at codon 254. It is amino-terminal of amino acid 830, so PVS1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3 - variant meets PM2 and was identified in 1 index case (Patient F3) with LDLc 18.21 mmol/l and compound heterozygote with NM_000527.5(LDLR):c.1216C>A (p.Arg406=) from Du et al. 2016 (PMID: 28028493). -- 2nd variant is classified as Likely Pathogenic by these guidelines and patient has phenotype of homozygous FH, so PM3 is met. PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 14 (LDL of 18.21mmol/L and xanthomas), from Du et al. 2016 (PMID: 28028493), China, so PP4 is met.
Familial hypercholesterolemia Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gln254*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 23375686). ClinVar contains an entry for this variant (Variation ID: 251436). For these reasons, this variant has been classified as Pathogenic.
The c.760C>T p.(Gln254Ter) variant in LDLR is a nonsense variant predicted to cause a premature stop codon at amino acid 254, which is amino-terminal of amino acid 830 (PVS1_VERY STRONG). The variant is absent from gnomAD v4.1.0, so PM2_MODERATE is met. This variant has been reported in 3 unrelated FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol were excluded (PS4_SUPPORTING, PP4_SUPPORTING; PMIDs 27206941, 28235710, 31153816). This variant was also observed in an individual with a homozygous FH phenotype who had 1 other pathogenic variant in LDLR in trans (PM3_MODERATE; PMID: 28028493). Based on the evidence listed above, we have classified this variant as Pathogenic.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at