rs193922567
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000527.5(LDLR):c.1358+2T>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000527.5 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1358+2T>A | splice_donor_variant, intron_variant | Intron 9 of 17 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1358+2T>A | splice_donor_variant, intron_variant | Intron 9 of 17 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461612Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727116 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6
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This variant causes a T to A nucleotide substitution at the +2 position of intron 9 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional RNA studies have not been reported for this variant, it is expected to cause aberrant splicing and result in an absent or disrupted protein product.. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11196104, 11462246, 21310417, 22698793, 22883975, 28008010). This variant has been identified in 1/245944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
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subject mutated among 2600 FH index cases screened = 1 -
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Familial hypercholesterolemia Pathogenic:6
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Variant summary: LDLR c.1358+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251086 control chromosomes. c.1358+2T>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Weiss_2000, Nauck_2001, Tichy_2012, Leren_2021, etc.). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=10) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
This variant causes a T to A nucleotide substitution at the +2 position of intron 9 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional RNA studies have not been reported for this variant, it is expected to cause aberrant splicing and result in an absent or disrupted protein product.. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11196104, 11462246, 21310417, 22698793, 22883975, 28008010). This variant has been identified in 1/245944 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The c.1358+2T>A variant in the LDLR gene is predicted to disrupt a canonical splice site and thus alter the wild type mRNA splicing. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID 11196104, 11462246, 15199436, 16250003, 21310417) and is absent from general population databases. Therefore, this c.1358+2T>A variant in the LDLR gene is classified as pathogenic. -
This sequence change affects a donor splice site in intron 9 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs193922567, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with LDLR-related conditions (PMID: 11196104, 11462246, 12124988, 21310417). 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. ClinVar contains an entry for this variant (Variation ID: 36455). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
LDLR c.1358+2T>A is a variant in the canonical splice donor site of exon 9 and is predicted to cause aberrant splicing although it is unknown whether the reading frame would be disrupted (PVS1_STRONG). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE) and has been reported in >=10 FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 11196104, 11462246, 16250003, 22698793, 32770674, 33508743). Based on the evidence listed above, we have classified this variant as Pathogenic. -
not provided Pathogenic:4
The LDLR c.1358+2T>A variant disrupts a canonical splice-donor site and interferes with normal LDLR mRNA splicing. This variant has been reported in the published literature in multiple individuals and families with familial hypercholesterolemia (PMIDs: 11196104 (2000), 11462246 (2001), 22698793 (2012), 22883975 (2012), 32770674 (2020), 33740630 (2021), 34037665 (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. -
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The LDLR c.1358+2T>A variant (rs193922567) is reported in the literature in multiple individuals affected with familial hypercholesterolemia (Leren 2021, Nauck 2001, Rieck 2020, Tichy 2012, Weiss 2000). This variant is also reported in ClinVar (Variation ID: 36455) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 9, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Leren TP et al. Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. Atherosclerosis. 2021 Apr;322:61-66. PMID: 33740630. Nauck MS et al. Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. Hum Mutat. 2001 Aug;18(2):165-6. doi: 10.1002/humu.1171. PMID: 11462246 Rieck L et al. Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. Clin Genet. 2020 Nov;98(5):457-467. PMID: 32770674. Tichy L et al. The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. Atherosclerosis. 2012 Aug;223(2):401-8. PMID: 22698793. Weiss N et al. Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia. J Inherit Metab Dis. 2000 Dec;23(8):778-90. PMID: 11196104. -
Identified in several unrelated individuals from different ethnic backgrounds with FH in published literature (Weiss et al., 2000; Nauck et al., 2001; Fouchier et al., 2005; Duskova et al., 2011; Tichy et al., 2012; Hooper et al., 2012) and in several patients with FH referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11196104, 21310417, 11462246, 12124988, 16250003, 15199436, 22883975, 22698793, 34040191, 33740630, 32770674, 34037665, 35913489) -
Homozygous familial hypercholesterolemia Pathogenic:1
The c.1358+2T>A variant in LDLR has been reported in 2 individuals with familial hypercholesterolemia and segregated with disease in both families (Weiss 2000, Nauck 2001). This variant has also been identified in 1/66288 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922567). However, this frequency is low enough to be consistent with the frequency of familial hypercholesterolemia in the general population. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in familial hypercholesterolemia. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon the predicted impact to the protein. -
Dyslipidemia Pathogenic:1
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See cases Pathogenic:1
ACMG categories: PVS1,PM2,PP5 -
Cardiovascular phenotype Pathogenic:1
The c.1358+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 9 in the LDLR gene. The mutation was detected in a patient diagnosed with familial hypercholesterolemia (FH) and in individuals from FH cohorts (Weiss N et al., J. Inherit. Metab. Dis. 2000 Dec; 23(8):778-90; Fouchier SW et al. Hum Mutat. 2005 Dec;26(6):550-6; Tichý L et al. Atherosclerosis. 2012 Aug;223(2):401-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at