chr19-11123248-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PVS1PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR) :c.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, 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:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PVS1 - Stop in codon 739. It is upstream of amino acid 830.PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Robarts Research Institute after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585809/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 stop_gained
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.2215C>T | p.Gln739* | stop_gained | Exon 15 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5Uncertain:1
The NM_000527.5(LDLR) :c.2215C>T (p.Gln739Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PVS1 - Stop in codon 739. It is upstream of amino acid 830. PP4 - Variant meets PM2 and is identified in one index case who fulfill FH/DLCN>=6 criteria for FH from Robarts Research Institute after alternative causes of high cholesterol were excluded. -
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subject mutated among 2600 FH index cases screened = 1/FH-Japan -
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Familial hypercholesterolemia Pathogenic:5
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The LDLR c.2215C>T p.(Gln739Ter) variant is a nonsense variant predicted to result in a stop codon at amino acid 739, which is amino-terminal of amino acid 830 (PVS1_VERY STRONG). This variant has been reported in FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol have been excluded (PS4_MODERATE, PP4_SUPPORTING; PMIDs 16314194, 20538126, 27765764, 28965616, 32220565, 32331935, 32423031, ClinGen FH VCEP data). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE). Based on the evidence listed above, we have classified this variant as Pathogenic. -
This variant (also known as Q718X) changes 1 nucleotide in exon 15 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID:12417285, 20045108, 20538126, 21376320, 23375686). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -
This sequence change creates a premature translational stop signal (p.Gln739*) 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 individuals with familial hypercholesterolemia (PMID: 12417285, 20045108, 20538126, 21376320, 23375686). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Gln718X. ClinVar contains an entry for this variant (Variation ID: 252258). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: LDLR c.2215C>T (p.Gln739X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251316 control chromosomes (gnomAD). c.2215C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Yu_2002, Robles-Osorio_2006, Romano_2010, Chiou_2010, Pirillo_2017, Kolansky_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reported that the variant resulted in less than 2% of normal LDLR activity in patient derived skin fibroblasts (Kolansky_2008). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and as VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
The LDLR c.2215C>T (p.Gln739*) variant causes the premature termination of LDLR protein synthesis. This variant has been reported in the published literature in multiple individuals with Familial Hypercholesterolemia (PMIDs: 12417285 (2002), 20538126 (2010), 21376320 (2011), 23375686 (2013), 28965616 (2017), 31491741 (2019), 32041611 (2020), 32331935 (2020), 32220565 (2020), 32423031(2020), 33303402 (2021), 33994402 (2021), 34297352 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Also known as p.(Q718*); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 32041611, 32331935, 32220565, 19026292, 28965616, 31491741, 33303402, 32423031, 23375686, 21376320, 20538126, 34037665, 20045108, 16314194, 12417285) -
Cardiovascular phenotype Pathogenic:1
The c.2215C>T (p.Q739*) alteration, located in exon 15 (coding exon 15) of the LDLR gene, consists of a C to T substitution at nucleotide position 2215. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 739. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in numerous individuals suspected to have familial hypercholesterolemia (FH) (Yu, 2002; Robles-Osorio, 2006; Kolansky, 2008; Chiou, 2010; Romano, 2010; Bertolini, 2013; Wang, 2016; Semenova, 2020; Tada, 2020; Di Taranto, 2021; Gill, 2021; Huang, 2022). Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at