rs794728584

Variant names:

• chr19-11120162-T-A
• rs794728584
• NM_000527.5:c.1916T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11120162-T-A
• chr19-11120162-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM3 PP1 PP4 PS4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1916T>A (p.Val639Asp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PM3, PP1 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).PS4, PP4: Variant meets PM2 and is identified in 10 unrelated index cases from different labs (2 cases with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 1 case with DLCN>=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with DLCN>=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with DLCN=9 from Germany (PMID 11462246 – Nauck et al., 2001); at least 1 case with definite FH from The Netherlands (PMID 16250003 – Fouchier et al., 2005); 1 case with DLCN>=6 from Argentina (PMID 28502510 – Bañares et al., 2017); 1 case with Simon Broome criteria for FH from Poland (PMID 35741760 – Rutkowska et al. 2022); 1 true homozygous case with clinical diagnosis of HoFH from Spain (PMID 27784735); 1 case with homozygous FH phenotype (LDL-C= 13.52 mmol/L) from Germany (PMID 29502162).PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic: 2 affected family members have the variant.PM3: Variant meets PM2 and is identified in 1 index case with homozygous FH phenotype (LDL-C=11.7 mmol/L) and LDLR c. 2043C>T/p.(Cys681*), classified as Pathogenic by these guidelines, in trans, from Germany (PMID 29502162 – Klaus et al., 2018). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023607/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:4
• Conservation: PhyloP100: 7.85

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 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1916T>A	p.Val639Asp	missense_variant	Exon 13 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1916T>A	p.Val639Asp	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:3

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Iberoamerican FH Network

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2025

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.1916T>A (p.Val639Asp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PM3, PP1 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PS4, PP4: Variant meets PM2 and is identified in 10 unrelated index cases from different labs (2 cases with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 1 case with DLCN>=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case with DLCN>=6 from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with DLCN=9 from Germany (PMID 11462246 – Nauck et al., 2001); at least 1 case with definite FH from The Netherlands (PMID 16250003 – Fouchier et al., 2005); 1 case with DLCN>=6 from Argentina (PMID 28502510 – Bañares et al., 2017); 1 case with Simon Broome criteria for FH from Poland (PMID 35741760 – Rutkowska et al. 2022); 1 true homozygous case with clinical diagnosis of HoFH from Spain (PMID 27784735); 1 case with homozygous FH phenotype (LDL-C= 13.52 mmol/L) from Germany (PMID 29502162). PP1: Variant segregates with FH phenotype in 2 informative meiosis from 1 family from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic: 2 affected family members have the variant. PM3: Variant meets PM2 and is identified in 1 index case with homozygous FH phenotype (LDL-C=11.7 mmol/L) and LDLR c. 2043C>T/p.(Cys681*), classified as Pathogenic by these guidelines, in trans, from Germany (PMID 29502162 – Klaus et al., 2018). -

Jul 23, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1 Uncertain:1

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.1916T>A (p.Val639Asp) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (FH) (PMID: 11462246 (2001), 16250003 (2005), 28502510 (2017), 29502162 (2018), 30293936 (2018), 32770674 (2020), 35222550 (2020), 35741760 (2022)). In addition, an individual with a diagnosis of homozygous FH (HoFH) was reported as being positive for two copies of this variant (PMID: 27784735 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Oct 29, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V639D variant (also known as c.1916T>A), located in coding exon 13 of the LDLR gene, results from a T to A substitution at nucleotide position 1916. The valine at codon 639 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant (also described as legacy p.V618D) has been reported in familial hypercholesterolemia (FH) cohorts, and has been detected in both heterozygous and homozygous FH cases (Nauck MS et al. Hum Mutat. 2001;18(2):165-6; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Bañares VG et al. J Clin Lipidol 2017 Mar;11:524-531; Rutkowska L et al. Genes (Basel), 2022 Jun;13:). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is likely to be pathogenic. -

Familial hypercholesterolemia Pathogenic:1

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 639 of the LDLR protein (p.Val639Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11462246, 16250003, 28502510, 32770674; Invitae). This variant is also known as V618D. ClinVar contains an entry for this variant (Variation ID: 200922). 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%. This variant disrupts the p.Val639 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 22311046), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.
Eigen	Benign	0.096
Eigen_PC	Benign	0.066
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;M
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.024	B;.;.;.;.;.
Vest4		0.74
MutPred		0.89		Gain of disorder (P = 0.0039);Gain of disorder (P = 0.0039);.;.;.;Gain of disorder (P = 0.0039);
MVP		1.0
MPC		0.48
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs794728584; hg19: chr19-11230838;