rs72658865

Variant names:

• chr19-11116969-G-A
• rs72658865
• NM_000527.5:c.1816G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11116969-G-A
• chr19-11116969-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR): c. 1816G>A (p.Ala606Thr) variant is classified as Uncertain significance -insufficient evidence for Familial Hypercholesterolemia as no evidence codes were met as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 not Met: PopMax MAF = 0.0002024 in Latino population in gnomAD (gnomAD v2.1.1), and PopMAX MAF = 0.00043 in Latino population in ExAC (ExAC v0.3.1).PP3 not Met: REVEL = 0.725, which is below 0.75. Functional data on splicing is not available, in silico splicing prediction is required. The variant is exonic and located at least 50 bases downstream of authentic acceptor site, but it does not create GT. The variant is not on limit creating de novo acceptor site. Therefore, this variant is not predicted to alter splicing.BP4 not applicable: REVEL score for this variant is not below 0.5, BP4 is not applicable.PP4, PS4 not applicable: Variant did not meet PM2.PM5 not met: There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1817C>A (p.Ala606Asp), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA036744/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:6 B:1
• Conservation: PhyloP100: 1.67

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1816G>A	p.Ala606Thr	missense_variant	Exon 12 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1816G>A	p.Ala606Thr	missense_variant	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251476 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

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: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000567

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:6 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:3 Benign:1

Mar 23, 2017

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 606 of the LDLR protein. This variant is also known as p.Ala585Thr in the mature protein. This variant alters a conserved alanine residue in the LDLR type B repeat 5 of the EGF precursor homology domain of the LDLR protein (a.a. 572 - 615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 17087781, 19318025, 27784735, 29233637, 30293936, 32660911). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 29233637), as well as in homozygous state in another individual affected with a severe phenotype (PMID: 11484166). This variant has been identified in 9/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 08, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5 (LDLR): c. 1816G>A (p.Ala606Thr) variant is classified as Uncertain significance -insufficient evidence for Familial Hypercholesterolemia as no evidence codes were met as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 not Met: PopMax MAF = 0.0002024 in Latino population in gnomAD (gnomAD v2.1.1), and PopMAX MAF = 0.00043 in Latino population in ExAC (ExAC v0.3.1). PP3 not Met: REVEL = 0.725, which is below 0.75. Functional data on splicing is not available, in silico splicing prediction is required. The variant is exonic and located at least 50 bases downstream of authentic acceptor site, but it does not create GT. The variant is not on limit creating de novo acceptor site. Therefore, this variant is not predicted to alter splicing. BP4 not applicable: REVEL score for this variant is not below 0.5, BP4 is not applicable. PP4, PS4 not applicable: Variant did not meet PM2. PM5 not met: There are two other variants in same codon: LDLR: NM_000527:c1816G>T (p.Ala606Ser), LDLR: NM_000527:c.1817C>A (p.Ala606Asp), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met. -

Familial hypercholesterolemia Pathogenic:2 Uncertain:1

Sep 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 606 of the LDLR protein. This variant is also known as p.Ala585Thr in the mature protein. This variant alters a conserved alanine residue in the LDLR type B repeat 5 of the EGF precursor homology domain of the LDLR protein (a.a. 572 - 615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with familial hypercholesterolemia (PMID: 17087781, 19318025, 27784735, 29233637, 30293936, 32660911), including in cases of severe familial hypercholesterolemia in the homozygous state and compound heterozygous state with a second pathogenic variant (PMID: 11484166, 29233637). This variant has been identified in 9/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 606 of the LDLR protein (p.Ala606Thr). This variant is present in population databases (rs72658865, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 19318025, 23340035, 36105085; internal data). 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 benign with a negative predictive value of at least 95%. 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: 252046). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Ala606 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 36105085; internal data). 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. -

Oct 15, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Apr 04, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 28502495, 23340035, 19020990, 30312929, 19318025, 30108616, 11484166, 7903864, 29233637, 32660911, 16092059, 34815205, 35725860, 27784735) -

not specified Uncertain:1

Feb 05, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1816G>A (p.Ala606Thr) results in a non-conservative amino acid change in 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 3.6e-05 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1816G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia and undertaking genetic testing based on familial/personal hypercholesterolemia (examples, Alonso_2009, Medel_2012, Velilla_2022), not all of which has provided sufficient information for analysis. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19318025, 23340035, 36105085). ClinVar contains an entry for this variant (Variation ID: 252046). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A606T variant (also known as c.1816G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1816. The alanine at codon 606 is replaced by threonine, an amino acid with similar properties. This alteration, which is also known as p.A585T, has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited in some cases (Chiu CY et al. Metabolism, 2005 Aug;54:1082-6; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Viladés Medel D et al. Am. J. Cardiol., 2013 Apr;111:955-61; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Ibarretxe D et al. Atherosclerosis, 2018 11;278:210-216; Ma Y et al. J Clin Lipidol 2018 Oct;12:230-235.e6; Lamiquiz-Moneo I et al. Rev Esp Cardiol (Engl Ed), 2021 Aug;74:664-673). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.0098
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.5	L;.;.;.;.;L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;D;N;N;N;D
REVEL	Pathogenic	0.72
Sift	Benign	0.034	D;T;D;D;D;D
Sift4G	Benign	0.079	T;T;T;T;T;T
Polyphen		0.33	B;.;.;.;.;.
Vest4		0.58
MutPred		0.81		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;.;.;Gain of sheet (P = 0.0477);
MVP		1.0
MPC		0.49
ClinPred		0.84	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.98

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: rs72658865; hg19: chr19-11227645;