19-11111514-A-T

Position:

chr19-11111514-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.1061A>T(p.Asp354Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,146 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D354A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense, splice_region

Scores

Splicing: ADA: 0.4141

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.21

Variant links:

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]

LDLR links:

LDLR (HGNC:):

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11111514-A-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 19-11111514-A-T is Pathogenic according to our data. Variant chr19-11111514-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11111514-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.1061A>T	p.Asp354Val	missense_variant, splice_region_variant	8/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1061A>T	p.Asp354Val	missense_variant, splice_region_variant	8/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461020

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726840

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolemia (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic individuals have an earlier and more severe onset (GeneReviews). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium-binding EGF-like domain (NCBI). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Three alternative changes at the same codon have been reported in multiple individuals with familial hypercholesterolemia (ClinVar, PMID: 29353225). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with familial hypercholesterolemia (ClinVar, PMID: 1301956). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies using fibroblast has demonstrated reduced LDL receptor activity (PMID: 1301956). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 21, 2023	PP3, PP4, PM2_moderate, PM5, PS3_supporting, PS4_supporting -
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, PCSK9 and LDLRAP1. Results showed that the following variant was identified (see report below): p.Asp354Val (c.1061A>T) in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given case data, functional studies and other pathogenic variants at this same amino acid (p.Asp354Gly and p.Asp354Ala) we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least four unrelated cases of FH (not including this patient's family). There is good case data. This variant is historically known as p.Asp333Val. Hobbs, et al., 1992 (PMID: 1301956) reported this variant in a patient of American indian background and had 15-30 % of receptor activity. They classify this variant as a class 5, recycling defect allele. These bind and internalize ligands in coated pits, but fail to release the ligands in the endosome and thus do not recycle to the cell surface. They classify this variant as FH Oklahoma. Wittall, et al., 2010 (PMID: 19837725) reported this in one of their Greek patients with FH. Invitae has also seen this variant in multiple patients with FH. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 1.000). The Asp at codon 354 is conserved across species, as are neighboring amino acids. This variant is the first amino acid of the EGF-like 2 calcium binding domain. There is one individual with variation at codon 354 listed 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, Latino, and Ashkenazi descent. This indicates that variants at this position are rare. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2024	Identified in association with hypercholesterolemia and early-onset myocardial infarction in published literature and in ClinVar (PMID: 32220565, 1301956, 15556093, 19837725, 30586733, 32041611, 34037665); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D333V) and FH Oklahoma; This variant is associated with the following publications: (PMID: 17142622, 1301956, 32041611, 15556093, 30586733, 34037665, 19837725, 32220565) -

Familial hypercholesterolemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2018	Variant summary: LDLR c.1061A>T (p.Asp354Val) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Other variants have been reported as pathogenic or likley pathogenic in the same codon, suggesting a functional role of the codon (c.1061A>G, p.Asp354Gly; c.1061A>C, pAsp354Ala)The variant allele was found at a frequency of 6.5e-05 in 30944 control chromosomes. c.1061A>T has been reported in the literature in an individual affected with Familial Hypercholesterolemia who had reduced LDLR activity (Hobbs_1992). Three 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 354 of the LDLR protein (p.Asp354Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 19837725). This variant is also known as Asp333Val. ClinVar contains an entry for this variant (Variation ID: 251640). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Asp354 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20145306, 20809525, 22698793). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 11, 2019	This missense variant (also known as p.Asp333Val in the mature protein) is located in the EGF-like repeat A in the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional assays have shown that this variant significantly reduces LDLR activity in cells from a heterozygous patient (PMID: 1301956). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 1301956, 17142622, 19837725). This variant has been identified in 2/30944 chromosomes (2/14980 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

The p.D354V variant (also known as c.1061A>T) is located in coding exon 8 of the LDLR gene. The aspartic acid at codon 354 is replaced by valine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 8. This variant (also referred to as p.D333V) has been detected in individuals and cohorts with familial hypercholesterolemia (FH), and in individuals undergoing genetic testing for suspicion of FH (Sozen M et al. Atheroscler Suppl, 2004 Dec;5:7-11; Humphries SE et al. J Med Genet, 2006 Dec;43:943-9; Brown EE et al. J Clin Lipidol, 2020 Mar;14:331-338; Sturm AC et al. JAMA Cardiol, 2021 Aug;6:902-909; Ambry internal data). This variant was detected in an individual from an FH cohort demonstrating 15-30% LDLR activity who was indicated as being compound heterozygous for another, unidentified allele (Hobbs HH et al. Hum Mutat, 1992;1:445-66). Another alteration at the same codon, p.D354G (c.1061A>G, also referred to as p.D333G), has also been reported in association with FH (Mosig S et al. BMC Med Genomics. 2008 Nov;1:60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

D;.;.;.;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;H

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-8.4

D;D;D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.96

MutPred

0.94

Loss of disorder (P = 0.0185);Loss of disorder (P = 0.0185);.;.;.;Loss of disorder (P = 0.0185);

MVP

1.0

MPC

0.98

ClinPred

1.0

GERP RS

5.5

Varity_R

0.97

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.41

dbscSNV1_RF

Benign

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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