chr19-11102787-G-A

Position:

• chr19-11102787-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PP4 PS3_Moderate PS4 PP1_Strong PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000527.4(LDLR):c.313+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1_Strong, PS4, PP1_Strong, PM2, PS3_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - Variant is in canonical GT +1 splice site, predicted to lead to exon 3 skipping (in frame).PS4 - Variant meets PM2. Identified in at least 14 unrelated index cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCS equal or above 6. PP1_strong - variant segregates with FH phenotype in 6 informative meiosis in 5 families from different laboratories. PM2 - PopMax MAF = 0.00006156 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1).PS3_moderateLevel 2 assays: PMID 19361455: Hmz patients' Epstein-Barr tranformed lymphocytes, RNA and FACS assays - results - Alternative splicing: skipping of exon 3 or inclusion of intron 3; amount of cell-surface LDLR 33% of normal (Hmz); 12% LDL-LDLR uptake in Hmz ---- Aberrant transcripts confirmed by sequencing and above 25% of total transcript, and uptake is below 70% of wild-type, so PS3_moderate is Met.PP4 - Variant meets PM2. Identified in 3 FH cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria and in 13 FH cases from University of British Columbia (UBC, Canada) and 14 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023688/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: LDLR NM_000527.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:37 B:1 O:1
• Conservation: PhyloP100: 8.10

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.313+1G>A		splice_donor_variant		ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.313+1G>A		splice_donor_variant		1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251424 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1460880 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 726744

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:23 Benign:1

Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 16, 1996	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 09, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 08, 2021	ACMG classification criteria: PVS1 strong, PS3 supporting, PS4 strong, PM2 moderate, PP1 strong, PP4 supporting -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Sep 25, 2014	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 07, 2021	The NM_000527.4(LDLR):c.313+1G>A variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1_Strong, PS4, PP1_Strong, PM2, PS3_Moderate and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1_strong - Variant is in canonical GT +1 splice site, predicted to lead to exon 3 skipping (in frame). PS4 - Variant meets PM2. Identified in at least 14 unrelated index cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with DLCS equal or above 6. PP1_strong - variant segregates with FH phenotype in 6 informative meiosis in 5 families from different laboratories. PM2 - PopMax MAF = 0.00006156 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate Level 2 assays: PMID 19361455: Hmz patients' Epstein-Barr tranformed lymphocytes, RNA and FACS assays - results - Alternative splicing: skipping of exon 3 or inclusion of intron 3; amount of cell-surface LDLR 33% of normal (Hmz); 12% LDL-LDLR uptake in Hmz ---- Aberrant transcripts confirmed by sequencing and above 25% of total transcript, and uptake is below 70% of wild-type, so PS3_moderate is Met. PP4 - Variant meets PM2. Identified in 3 FH cases from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge who fulfill Simon-Broome criteria and in 13 FH cases from University of British Columbia (UBC, Canada) and 14 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with clinical Dutch Lipid Clinic Network Criteria score ≥ 6. -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/208 non-FH alleles; 0/100 healthy control individuals -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19361455). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000003736). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Nov 20, 2023	PVS1_strong, PP1_strong, PS4, PM2, PP4, PS3_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The splice site variant c.313+1G>A in LDLR gene has been reported previously in heterozygous state in individuals affected with Familial hypercholesterolemia (Trinder M, et al., 2019, Zakharova FM, et al., 2005). Experimental evidence shows that this variant results in two mutant transcripts, one has skipping of exon 3 and the other has inclusion of intron 3. The transcript with skipping of exon 3 was demonstrated to have considerably reduced cell-surface LDLR and total amounts of internalized LDL, indicating that the variant LDLR is markedly dysfunctional (Cameron J, et al., 2009). The variant has 0.003% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar as Likely Benign, Likley Pathogenic, Pathogenic (multiple submissions).This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 21, 2017	The c.313+1G>A variant in LDLR gene destroys the canonical splice donor site in intron 3 and is predicted to result in abnormal splicing of the LDLR message. Functional studies have shown that the c.313+1G>A variant disrupts mRNA splicing and produces a protein with abnormal function (PMID 19361455). This variant has been reported in multiple unrelated individuals with hypercholesterolemia (PMID 7718019, 22390909, 22883975, 20045108, 20145306, 15523646) and individuals with early-onset myocardial infarction (PMID 25487149). This variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 4/FH-Europe -
Pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -

not provided Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2022	PP3 -
not provided, no classification provided	literature only	SNPedia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 03, 2023	This variant disrupts a canonical splice-donor site and interferes with normal LDLR mRNA splicing (PMID: 19361455 (2009)). The frequency of this variant in the general population, 0.000062 (7/113710 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals with familial hypercholesterolemia (FH) (PMID: 25487149 (2015), 22390909 (2012), 20045108 (2010), 14974088 (2004), 7616128 (1995)), and has been shown to segregate with disease (PMID: 8829662 (1996)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2022	Described as a founder mutation in the Norwegian population (Leren et al., 1994); Published functional studies demonstrate that c.313+1 G>A leads to the production of two abnormal transcripts which impair LDL receptor function (Cameron et al., 1999); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#3736; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD; other references); This variant is associated with the following publications: (PMID: 25525159, 25487149, 10735632, 22883975, 30592178, 30795984, 31048103, 22390909, 10634824, 17765246, 7616128, 20145306, 20045108, 10532689, 14974088, 7718019, 25468658, 29233637, 31447099, 8911609, 32041611, 33303402, 32719484, 33226606, 33740630, 34037665, 19361455) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 30, 2017	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 09, 2017	Genetic testing: The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results reported on October 17, 2017 showed that the following variant was identified (see report below): c.313+1G>A in the LDLR gene (NM_000527.4) Ambry classifies this variant as pathogenic. Given sufficient case data and functional in vitro studies, we consider this variant very likely disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is a common cause of FH around the world. It is referred to as the FH-Elverum allele and the FH-Olbia allele. It's been identified in multiple populations around the world including Austria, Belgium, Denmark, Germany, Italy, Spain, Korea, Norway, The Netherlands, Russia, UK, Sweden, and South Africa (black). It's been identified in up to 25% of Norwegian FH patients and 5% of Western Australian patients. IT has also been reported in a case of homozygous FH. It has been written about in 14 publications and is listed as pathogenic or likely pathogenic by all seven entries in clinvar. An in vitro study found this mutation leads to several alternatively spliced transcripts, one of which skips exon 3 and can result in an abnormal LDLR protein with reduced function (Cameron et al. Clin Chim Acta. 2009. 403(1-2):13-15). This variant is located near a CpG enriched region which may be a mutational hot spot. This variant likely leads to loss of function of the LDL-receptor given its exon skipping nature. There are seven individuals with variation at c.313+1 position listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on 126,184 unrelated individuals at this position who are of African, Asian, European, Latino, and Ashkenazi descent. All 7 individuals are of European descent. This corresponds to about 1 in 8,015 European individuals in the general population which confirms that it's likely a common cause of FH in the European populations. -

Familial hypercholesterolemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2020	Variant summary: LDLR c.313+1G>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: Four predict the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that this variant results in two mutant transcripts, one has skipping of exon 3 and the other has inclusion of intron 3 (Cameron_2009, Jensen_1996). The transcript with skipping of exon 3 was demonstrated to have considerably reduced cell-surface LDLR and total amounts of internalized LDL, indicating that the variant LDLR is markedly dysfunctional (Cameron_2009). The variant allele was found at a frequency of 2.8e-05 in 251424 control chromosomes (gnomAD). c.313+1G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Deiana_2000, Jensen_1996, Mozas_2004, Leren_1994). These data indicate that the variant is very likely to be associated with disease. Fourteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=13) and as likely benign (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 07, 2023	This variant (also known as FH-Elverum) causes a G to A nucleotide substitution at the +1 position of intron 3 of the LDLR gene, and is predicted to abolish the intron 3 canonical splice donor site. An experimental study has shown that this variant causes skipping of exon 3 and inclusion of intron 3, and no functional LDLR protein was produced from the mutant transcript (PMID: 19361455). The variant has been reported in over 500 individuals affected with familial hypercholesterolemia (PMID: 7616128, 7718019, 10532689, 14974088, 15241806, 16159606, 17539906, 17765246, 20045108, 20145306, 22883975, 28502510, 29233637, 29353225, 30795984, 33740630, 34037665) and is considered to be a founder mutation in the Norwegian population (PMID: 7718019, 33740630). In addition, a large case-control study has shown that this variant is associated with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 7/251424 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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change affects a donor splice site in intron 3 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs112029328, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 10532689, 15701167, 19361455). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3736). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 19361455). For these reasons, this variant has been classified as Pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 26, 2019

The c.313+1G>A variant in LDLR has been reported in >140 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 5 affected relatives from 2 families (Leren 1994, Sun 1995, Lombardi 2000, Hooper 2012). This variant has also been identified in 7/111670 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. The c.313+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing that would preserve the protein reading frame, leading to an abnormal protein. Furthermore, in vitro functional studies provide some evidence that this variant may impact protein function (Sun 1995, Cameron 2009). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in the general population, and impact to the protein. The ACMG/AMP Criteria applied: PS4, PM2, PP1_Moderate, PVS1_Moderate. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 21, 2021

ACMG categories: PVS1,PM2,PP5 -

LDLR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

The LDLR c.313+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is a well-documented pathogenic variant for familial hypercholesterolemia (see for example Chan et al. 2018. PubMed ID: 30592178; Luirink et al. 2018. PubMed ID: 30795984; Jensen et al. 1999. PubMed ID: 10532689; Lombardi et al. 2000. PubMed ID: 10735632; Chmara et al. 2010. PubMed ID: 20145306; Mozas et al. 2004. PubMed ID: 15241806; Alonso et al. 2009. PubMed ID: 19318025; Lombardi et al. 1995. PubMed ID: 7616128). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

The c.313+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 of the LDLR gene. 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. Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/251424) total alleles studied. The highest observed frequency was 0.006% (7/113710) of European (non-Finnish) alleles. This mutation has been identified in both heterozygous and homozygous states in patients with classic familial hypercholesterolemia (FH) (Leren, 1994; Hartgers, 2018; Ibarretxe, 2018; Chan, 2019). This nucleotide position is highly conserved in available vertebrate species. An in vitro study found this mutation leads to several alternatively spliced transcripts, one of which skips exon 3 and can result in an abnormal LDLR protein with reduced function (Cameron, 2009). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	30
DANN	Uncertain	0.97
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs112029328; hg19: chr19-11213463; COSMIC: COSV52944686; COSMIC: COSV52944686;