rs28942078

Positions:

• chr19-11113376-G-A
• chr19-11113376-G-C
• chr19-11113376-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3 PP4 PS3_Moderate PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1285G>A (p.Val429Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows:PM2: PopMax MAF = 0.00003266 (0.003%) in South Asian exomes (gnomAD v2.1.1). PP3: REVEL = 0.809. PS3_Moderate: Level 2 assay – PMID 2569482 (Leitersdorf et al., 1989) - Immunoprecipitation assay on heterozygous CHO cells where the receptor was degraded more rapidly. After 6 h, only 13% of the LDL receptor protein remained. Level 2 assay – PMID 3202825 (Fourie et al., 1988) - 125I-labelled LDL assay on homozygous patient's fibroblasts with overall LDL receptor activity of ~2% of wildtype. PS4, PP4: Variant meets PM2 and is identified in at least 55 unrelated index cases who fulfill criteria for FH- 1 case with DLCN score >=6 from Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain;- 4 cases with DLCN score >=6 from Robarts Research Institute, Canada;- 9 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia;- 2 cases with DLCN score >=6 and 1 case with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France;- 2 cases with possible FH by Simon Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 36 cases fulfilling MEDPED criteria from PMID 8399083 (Kotze et al., 1993), South Africa. PP1_Strong: Variant segregates with FH phenotype in 27 informative meiosis from at least 10 families from different labs (Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain; Robarts Research Institute, Canada; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; Laboratory of Genetics and Molecular Cardiology, Brazil; PMID 26036859 (Brænne et al., 2016), Germany; PMID 21925660 (Versmissen et al., 2011), the Netherlands): 19 affected family members have the variant and 8 unaffected family members do not have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023443/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:30 O:1
• Conservation: PhyloP100: 2.72

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 14 ACMG points.

• 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.
• PP3: 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.1285G>A	p.Val429Met	missense_variant	9/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1285G>A	p.Val429Met	missense_variant	9/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251284 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome Cov.: 29

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:19

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Nov 07, 2011	- -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
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	May 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003694). A different missense change at the same codon (p.Val429Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000226353, VCV000251767). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely 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	subjects mutated among 2600 FH index cases screened = 12 , family members = 6 with co-segregation / FH-Afrikaner-2, < 2% LDLR Activity / Software predictions: Conflicting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant (also known as p.Val409Met and as FH Afrikaner-2) is located in the first LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that the mutant protein shows <2% LDLR activity (PMID: 1301956, 3202825, 6324732). While this variant is rare in the general population (1/120888 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 1301956, 1952806, 7649549, 8478013, 9763532, 6324732, 7903269, 19837725, 20506408, 21722902, 23375686, 26036859). This variant is considered to be a founder mutation in the South Afrikaner population (PMID: 1757095, 2569482). Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 27, 2023	The NM_000527.5(LDLR):c.1285G>A (p.Val429Met) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PS3_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003266 (0.003%) in South Asian exomes (gnomAD v2.1.1). PP3: REVEL = 0.809. PS3_Moderate: Level 2 assay – PMID 2569482 (Leitersdorf et al., 1989) - Immunoprecipitation assay on heterozygous CHO cells where the receptor was degraded more rapidly. After 6 h, only 13% of the LDL receptor protein remained. Level 2 assay – PMID 3202825 (Fourie et al., 1988) - 125I-labelled LDL assay on homozygous patient's fibroblasts with overall LDL receptor activity of ~2% of wildtype. PS4, PP4: Variant meets PM2 and is identified in at least 55 unrelated index cases who fulfill criteria for FH - 1 case with DLCN score >=6 from Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain; - 4 cases with DLCN score >=6 from Robarts Research Institute, Canada; - 9 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; - 2 cases with DLCN score >=6 and 1 case with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France; - 2 cases with possible FH by Simon Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 36 cases fulfilling MEDPED criteria from PMID 8399083 (Kotze et al., 1993), South Africa. PP1_Strong: Variant segregates with FH phenotype in 27 informative meiosis from at least 10 families from different labs (Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain; Robarts Research Institute, Canada; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; Laboratory of Genetics and Molecular Cardiology, Brazil; PMID 26036859 (Brænne et al., 2016), Germany; PMID 21925660 (Versmissen et al., 2011), the Netherlands): 19 affected family members have the variant and 8 unaffected family members do not have the variant. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 07, 2018	The best available variant frequency is uninformative. Statistically enriched in patients compared to controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2023	Described as one of the two founder mutations that account for approximately 80% of FH cases in the Afrikaner population (Kotze et al., 1993); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect with slower processing of precursor LDLR protein to the mature protein and faster degradation of the protein (Leitersdorf et al., 1989); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as p.(V408M) FH Afrikaner-2; This variant is associated with the following publications: (PMID: 25741868, 20506408, 26036859, 11139254, 22390909, 32759540, 35339733, 21925660, 8478013, 7718024, 9763532, 7903269, 8096412, 1952806, 21475731, 11668627, 11196104, 19837725, 28492532, 15199436, 21722902, 11325764, 7649549, 15256764, 32041611, 33303402, 32719484, 33740630, 33418990, 33599434, 33087929, 8399083, 35379577, 34426522, 30241732, 34037665, 34456049, 23375686, 2569482, 35913489) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 10, 2021	PP1_strong, PS4_moderate, PS3_moderate, PM3, PP3, PP4 -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 12, 2017	p.Val429Met (c.1285G>A; also known as Val408Met or V408M in the literature) in the LDLR gene (NM_000527.4) Given the strong case data for this founder variant, its location in the LDL receptor protein and its rarity in large population databases, we consider this variant disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 204 unrelated cases of FH (not including this patient's family). There is very strong case data. There are likely many more cases of this variant given that it is a Dutch founder variant. This variant is classified as likely pathogenic or pathogenic by 6 submitters. It was seen in at least 34 individuals submitted by these groups, including 2 individuals from one family. This variant was found in a very large (8-generation, 412-member) Dutch family. 161 members of this family were found to have the variant and high cholesterol levels above the 95th percentile. Furthermore, this group identified a genotype-phenotype correlation: when V408M is maternally transmitted it is associated with a 2-fold increase in mortality risk in untreated individuals with FH. (Versmissen et al 2011). This variant was found in one out of 60 individuals from Ontario, Canada. This patient had Dutch ancestry. This variant was found in 2 of 1070 (of which 52 were homozygotes) Italian individuals with FH (Bertolini et al 2013). This variant was found in 1 Afrikans individual with homozygous FH (of Dutch ancestry), and these authors concluded that the p.Val429Met variant is a Dutch founder variant (Leitersdorf et al. 1989). This variant was identified in 1 of 25 German patients with FH. This variant was found in 4 of 28 individuals of Greek descent, ranging from 34 to 57 years old (Whittal et al 2009). This variant completely abolishes receptor function (Hobbs et al 1992). The valine at codon 429 is almost completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Val429Leu) nearby codons (p.Asn425Ile, p.Asn425Thrfs, p.Ala431Terfs, p.Ala431Pro, p.Ala431 Thr, p.Leu431Val, p.432Pro, p.Asp433del, p.Asp433Tyr, p.Asp433His). The variant was reported online in 3 of 123,065 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 15,391 individuals of South Asian descent (MAF=0.0032%), 1 of 12,290 individuals of Latino descent and 1 of 55,800 individuals of European (non-Finnish) descent. 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). -

Familial hypercholesterolemia Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2022	Variant summary: LDLR c.1285G>A (p.Val429Met) results in a conservative amino acid change located in the LDLR class B repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251284 control chromosomes. c.1285G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. This publication reported cells carrying the variant processed the LDL receptor protein more slowly and degraded the protein more rapidly compared to wild-type cells (Leitersdorf_1989). Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 06-19-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 429 of the LDLR protein (p.Val429Met). This variant is present in population databases (rs28942078, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2569482, 11139254, 11196104, 11668627, 15256764, 19837725, 21475731, 21925660, 23375686). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val408Met. ClinVar contains an entry for this variant (Variation ID: 3694). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 2569482). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 02, 2023	This missense variant replaces valine with methionine at codon 429 of the LDLR protein. This variant is also known as p.Val408Met in the mature protein and as FH Afrikaner-2. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein shows <2% LDLR activity (PMID: 6324732, 1301956, 2569482, 3202825,). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 1301956, 1952806, 7649549, 8478013, 9763532, 6324732, 7903269, 19837725, 20506408, 21722902, 23375686, 26036859, 2569482, 6324732, 8478013). It has been shown that this variant segregates with disease in multiple families (PMID: 2569482, 6324732, 8478013). This variant has been identified in 3/251284 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2019

The p.Val429Met variant in LDLR has been identified in over 25 individuals with familial hypercholesterolemia (FH; including in 2 homozygotes and 3 compound heterozygotes with a known pathogenic variant) and segregated with disease in over 100 affected relatives from at least 1 family (Leitersdorf 1989, Dedoussis 2004, Versmissen 2011). Additionally, this variant was also identified in at least 1 family (of 2 affected sibs) with premature myocardial infraction (MI; Braenne 2015). The p.Val429Met variant has been reported by other clinical laboratories in ClinVar (Variation ID: 3694) and has also been identified in 0.001% (3/251284) of pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro functional studies support an impact on protein function (Leitersdorf 1989). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting. -

LDLR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

The LDLR c.1285G>A variant is predicted to result in the amino acid substitution p.Val429Met. This variant has been reported in multiple individuals with hypercholesterolemia (for examples, see Leitersdorf et al. 1989. PubMed ID: 2569482, reported as p.Val408Met; Versmissen et al. 2011. PubMed ID: 21925660; Meshkov et al. 2021. PubMed ID: 33418990; Sturm et al. 2021. PubMed ID: 34037665, supplementary table 1). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.1285G>A (p.V429M) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1285, causing the valine (V) at amino acid position 429 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/251284) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This mutation has been reported in the homozygous and compound heterozygous states in numerous unrelated individuals from various ethnic backgrounds who met strict clinical diagnoses of familial hypercholesterolemia (Leitersdorf, 1989; Bertolini, 2013). In one Dutch study, three independently ascertained probands with this mutation were found to have the same haplotype and subsequently traced back seven generations to a common ancestor, resulting in a kindred of over 160 individuals and more than 10 obligate carriers of this mutation. All family members for whom untreated cholesterol levels were available were reported to have cholesterol levels above the 95th percentile (Sijbrands, 2001; Versmissen, 2011). In one functional study, cultured fibroblasts from an individual homozygous for this mutation exhibited an overall LDL receptor activity of only ~2% of wildtype (Fourie, 1988). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.9	L;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.020	D;D;D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.52
MutPred		0.86		Gain of phosphorylation at T434 (P = 0.1319);Gain of phosphorylation at T434 (P = 0.1319);.;.;.;Gain of phosphorylation at T434 (P = 0.1319);
MVP		1.0
MPC		0.77
ClinPred		0.82	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs28942078; hg19: chr19-11224052; COSMIC: COSV52944609; COSMIC: COSV52944609;