rs761954844

Variant names:

• chr19-11110697-G-A
• rs761954844
• NM_000527.5:c.986G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11110697-G-A
• chr19-11110697-G-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.986G>A​(p.Cys329Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. C329F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 B:1
• Conservation: PhyloP100: 9.68
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 18 uncertain in NM_000527.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11110697-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 251586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11110697-G-A is Pathogenic according to our data. Variant chr19-11110697-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 226344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.986G>A	p.Cys329Tyr	missense_variant	Exon 7 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.986G>A	p.Cys329Tyr	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152172 Hom.: 0 Cov.: 32

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250998 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000715 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7 Benign:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation;literature only

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Cys329Tyr variant in LDLR has been reported in at least 25 individuals (including 17 Taiwanese, 2 Russian, 2 Chinese, 1 Filipino, and 1 Czech individuals) with Familial Hypercholesterolemia (PMID: 22353362, 9763532, 11810272, 15701167, 16205024, 27765764, 22698793), and has been identified in 0.01003% (2/19938) of East Asian chromosomes and 0.005645% (2/35428) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761954844). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a likely benign variant, likely pathogenic variant, and pathogenic variant in ClinVar (Variation ID: 226344). In vitro functional studies with transfected COS cells provide some evidence that the p.Cys329Tyr variant may impact LDL receptor activity (PMID: 26608663). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant with a different amino acid change at the same position (p.Cys329Phe) has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 251586). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PS3_supporting, PM5_supporting, PP3 (Richards 2015). -

-

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2008

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disrupt disulfide bridge between Cys318 and Cys329. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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 benign

Review Status: flagged submission

Collection Method: clinical testing

subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?) / Software predictions: Damaging -

Familial hypercholesterolemia Pathogenic:3

Jul 17, 2024

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Based on the ACMG/AMP 2015 guidelines (Richards 2015), p.Cys329Tyr variant has the following pathogenicity criteria: PS3 - an in vitro functional study shows that the presence of this variant reduces LDL receptor activity to 31% in transfected COS cells (Chang 2003); PM1 - located in a critical and well-established functional domain of the LDLR (EGF-A) (Galicia-Garcia 2020); PM2 - detected in control samples of gnomAD v4.1.0 with a frequency of 0.0006197%; PP1 - segregated with FH in 4 relatives in 2 families (data from the Laboratory of Molecular Genetics, Moscow, Russia); PP3; PP4 (registered in patients with FH). According to the ClinGen guidelines for LDLR variant classification (Chora 2022): PS4 - variant is found in ≥10 unrelated FH cases, including in Russia (Jiang 2015 (n = 26), Meshkov 2021 and Vasilyev 2022 (n = 13)); PS3_Moderate - meets level 2 pathogenic functional study criteria (Chang 2003); PM1 - changes in 1 of 60 highly conserved cysteine residues (p.Cys329) (Chora 2022); PM2 - has a PopMax MAF ≤ 0.0002 (0.02%) in gnomAD (0.0006197% v4.1.0 gnomAD); PP1_Moderate - segregates with phenotype in 4 informative meioses in 2 family (data from the Laboratory of Molecular Genetics, Moscow, Russia); PP3 - REVEL score 0.965 (Liu 2011, Liu 2020); PP4 - identified in 8 probands with FH (diagnosis based on DLCN-criteria (Meshkov 2021)). Based on a combination of criteria, this variant is pathogenic. -

Apr 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 329 of the LDLR protein (p.Cys329Tyr). This variant is present in population databases (rs761954844, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452118, 30270359, 30592178, 31706281). It has also been observed to segregate with disease in related individuals. This variant is also known as C308Y. ClinVar contains an entry for this variant (Variation ID: 226344). 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%. For these reasons, this variant has been classified as Pathogenic. -

Feb 21, 2024

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.986G>A p.(Cys329Tyr) variant has been seen in >=10 FH patients meeting clinical criteria, including after alternative causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 9763532, 11810272, 22698793, 25846081, 27765764, 30270359, 33994402, 33418990, internal data). This variant has been shown to segregate with disease in >6 informative meioses in >1 family (PP1_STRONG; PMIDs 9452118, 12837857, 22353362, 31706281) and has been seen in a patient with homozygous FH where parental testing confirmed variants were in trans (PM3_MODERATE; PMID 12837857). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001003 in East Asian population, which is lower than the ClinGen FH VCEP threshold (=<0.0002), so PM2_MODERATE is met. This is a missense change of a highly conserved cysteine residue and meets PM2 (PM1_MODERATE). Functional studies in COS-7 cells showed this variant decreased LDL receptor activity to ~31% of wild type (PS3_MODERATE; PMID 12837857) and the REVEL score is 0.965 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. -

not provided Pathogenic:2

Apr 30, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.(C308Y); This variant is associated with the following publications: (PMID: 31706281, 30592178, 33269076, 32423031, 30270359, 32041611, 33303402, 33740630, 33994402, 9452118) -

Oct 23, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.986G>A; p.Cys329Tyr variant (rs761954844), also known as Cys308Tyr, is reported in the literature in multiple individuals and families affected with familial hypercholesterolemia (Alver 2019, Mak 1998, Miroshnikova 2021, Jiang 2015). Functional analyses show the variant protein had LDLR activity of ~30% of wildtype (Jiang 2015). This variant is reported in ClinVar (Variation ID: 226344) and is found in the general population with an overall allele frequency of 0.003% (7/282402 alleles) in the Genome Aggregation Database. The cysteine at codon 329 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.965). Based on available information, this variant is considered to be pathogenic. References: Alver M et al. Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia. Genet Med. 2019 May;21(5):1173-1180. PMID: 30270359. Mak YT et al. Possible common mutations in the low density lipoprotein receptor gene in Chinese. Hum Mutat. 1998;Suppl 1:S310-3. PMID: 9452118. Miroshnikova VV et al. Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing. Biomed Rep. 2021 Jan;14(1):15. PMID: 33269076. Jiang L et al. The distribution and characteristics of LDL receptor mutations in China: A systematic review. Sci Rep. 2015 Nov 26;5:17272. PMID: 26608663. -

Dyslipidemia Pathogenic:1

Sep 30, 2021

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Apr 23, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C329Y pathogenic mutation (also known as c.986G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 986. The cysteine at codon 329 is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Vill&eacute;ger L. Hum Mutat. 2002;20(2):81-7). This alteration, also referred to as p.C308Y, has been described in multiple individuals with FH from various geographical locations (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Punzalan FE et al. J. Atheroscler. Thromb., 2005;12:276-83; Zakharova FM et al. BMC Med. Genet., 2005 Feb;6:6; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Tich&yacute; L et al. Atherosclerosis, 2012 Aug;223:401-8; Fan LL et al. Appl. Biochem. Biotechnol., 2015 May;176:101-9). This alteration has also been reported to segregate with the disease in one family, and in vitro studies suggested that the alteration led to reduced surface protein expression and ligand binding (Chang JH et al. J. Lipid Res., 2003 Oct;44:1850-8). Furthermore, internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;.;.;.;.;H
PhyloP100		9.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-11	D;D;D;D;D;D
REVEL	Pathogenic	0.96
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		0.99
MutPred		0.96		Gain of catalytic residue at C329 (P = 0.0565);Gain of catalytic residue at C329 (P = 0.0565);.;.;.;Gain of catalytic residue at C329 (P = 0.0565);
MVP		1.0
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs761954844; hg19: chr19-11221373;