rs387906305

Positions:

• chr19-11105585-GAC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000527.5(LDLR):​c.680_681del​(p.Asp227GlyfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D227D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LDLR NM_000527.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.21

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11105585-GAC-G is Pathogenic according to our data. Variant chr19-11105585-GAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105585-GAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.680_681del	p.Asp227GlyfsTer12	frameshift_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.680_681del	p.Asp227GlyfsTer12	frameshift_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248472 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135240

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455398 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 722884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000722

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:9

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 02, 2023	The LDLR c.680_681del variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) This LDLR c.680_681del variant is located in exon 4/18 and is predicted to cause a shift in the reading frame at codon 227 introducing a premature termination codon 12 amino acids downstream. (PVS1) The variant has been reported in multiple probands with a clinical presentation of hypercholesterolaemia (PMID: 27680772 , 22883975, 23669246, 14974088) (PS4_Moderate). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs387906305) and in the HGMD database: CD931019. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 3731). -
Pathogenic, 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	subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 13, 2023	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.680_681del (p.Asp227Glyfs*12) variant in the LDLR gene has been detected in multiple patients with hypercholesterolemia [PMID 8093663, 14974088, 10559517]. This 2 bp deletion in exon 4 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant is rare and has not been detected in the ExAC database. This variant thus classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 09, 2008	- -
Pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 15, 2017	p.Asp227Glyfs*12 (c.680_681delAC) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216262-AC-) This variant is also known as 79-680delAC and p.D206fs in the literature. SCICD Classification: pathogenic variant based on mechanism of disease, strong case data and rarity in the general population. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data (not including our patient): at least 6 patients with FH. ClinVar: Classified as pathogenic or likely pathogenic by 5 labs: LDLR-LOVD, British Heart Foundation, Robarts Research Institute,University of Western Ontario, Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, m voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, CardiovasLaboratoriucular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital. Cases in the literature: Gudnason et al., 1993: 3 out of 200 patients with FH (2 of British origin, 1 Afrikaaner) Dedoussis et al., 2004: 1 out of 200 patients with FH (ancestry unclear - 100 German and 100 Greek patients). Wang et al., 2016: 1 out of 313 patients with FH. Bunn et al., 2002: A very similar deletion (c.679-680delAC) was present in 1 out of 150 patients with FH. Segregation data: none reported Functional data: none reported for this specific variant; however, truncating variants in LDLR are a known mechanism of disease. Conservation data: The asparagine at codon 227 is complete conserved across species. Neighboring amino acids are also completely conserved. Population data: Highest MAF in European population: 0.0009%. The variant was reported online in 1 of 122,394 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 55,342 individuals of European descent (MAF=0.0009). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2022	Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8093663, 31447099, 32770674, 32041611, 33087929, 34037665) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 08, 2019

The p.Asp227fs variant in LDLR has been reported in at least 9 individuals with hypercholesterolemia (Gudnason 1993, Graham 1999, Bunn 2002, Dedoussis 2004, Martin 2016) and has also been reported in ClinVar (Variation ID #3731). This variant has also been identified in 1/110684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs387906305). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 227 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals and low frequency in controls. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2020

The c.680_681delAC pathogenic mutation, located in coding exon 4 of the LDLR gene, results from a deletion of two nucleotides at nucleotide positions 680 to 681, causing a translational frameshift with a predicted alternate stop codon (p.D227Gfs*12). This alteration has been detected in individuals from cohorts with confirmed or suspected familial hypercholesterolemia (Gudnason V et al. Arterioscler Thromb. 1993;13:56-63; Graham CA et al. Atherosclerosis. 1999;147:309-16; Dedoussis GV et al. Hum Mutat. 2004;23:285-6; Hooper AJ et al. Atherosclerosis. 2012;224:430-4; Futema M et al. Atherosclerosis. 2017;260:47-55). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 09, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3731). This variant is also known as 679-680delAC and p.D206fs. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (FH) (PMID: 8093663, 11857755, 14974088, 27765764). This variant is present in population databases (rs387906305, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asp227Glyfs*12) 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906305; hg19: chr19-11216261;