NM_000527.5:c.693C>G

Variant names:

• chr19-11105599-C-G
• rs121908035
• NM_000527.5:c.693C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.693C>G (p.Cys231Trp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met.PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).PP3 - REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met.PP4 - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs.PS4_supporting - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585085/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDLR NM_000527.5 missense, splice_region
• Scores: Splicing: ADA: 0.001641
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: -0.338
• Publications: 8 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.693C>G	p.Cys231Trp	missense_variant, splice_region_variant	Exon 4 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.693C>G	p.Cys231Trp	missense_variant, splice_region_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 149990 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000102 AC: 121 AN: 1190490 Hom.: 0 Cov.: 33 AF XY: 0.0000837 AC XY: 50 AN XY: 597088

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000357 AC: 1 AN: 28026

American (AMR) AF: 0.0000237 AC: 1 AN: 42198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22388

East Asian (EAS) AF: 0.000121 AC: 4 AN: 32940

South Asian (SAS) AF: 0.0000370 AC: 3 AN: 81108

European-Finnish (FIN) AF: 0.0000472 AC: 2 AN: 42346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 0.000120 AC: 107 AN: 888506

Other (OTH) AF: 0.0000612 AC: 3 AN: 49026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000133 AC: 2 AN: 150132 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73418

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000243 AC: 1 AN: 41216

American (AMR) AF: 0.00 AC: 0 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4894

South Asian (SAS) AF: 0.00 AC: 0 AN: 4596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67534

Other (OTH) AF: 0.00 AC: 0 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

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

subject mutated among 2600 FH index cases screened = 1 , family member = 1 / Software predictions: Damaging -

Jun 07, 2021

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.693C>G (p.Cys231Trp) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Missense at codon 231. PM2 is Met and Cys231 is one of the 60 Cys residues listed, so PM1 is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.708. It is not above 0.75, splicing evaluation is required. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 5.84; canonical site wt = 7.67. Ratio variant/wt canonical: 5.84/7.67 = 0.761. --- ratio is below 0.8, so PP3 is Met. PP4 - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. PS4_supporting - Variant meets PM2. Variant identified in at least 3 unrelated index cases with Simon-Broome criteria for FH from different labs. -

Aug 16, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 20809525, 24956927). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. This missense substitution occurs at an amino acid position that is known to be critical to protein structure/function. Other missense substitutions at this amino acid residue have been previously reported in individual(s) with disease and classified as pathogenic, which supports the functional importance of this position (PMID: 19073363, 27830735, 10422804, 11313767, 22698793). -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

0/190 non-FH alleles -

Cardiovascular phenotype Pathogenic:1

Jan 02, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C231W pathogenic mutation (also known as c.693C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 693. The cysteine at codon 231 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant (also referred to as p.C210W) was reported in individual(s) with features consistent with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat. 2010;31:E1811-24; Norsworthy PJ et al. BMC Med Genet. 2014;15:70). 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 FH (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). Other variant(s) at the same codon, p.C231R (c.691T>C), p.C231G (c.691T>G), have been identified in individual(s) with features consistent with FH (Sundvold H et al. Hum Mutat. 1996;7:70-1; Wang L et al. Nutr Metab Cardiovasc Dis. 2009;19:391-400). This amino acid position is highly 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 supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;.;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.8	H;.;.;H
PhyloP100		-0.34
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-9.8	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.76		Gain of catalytic residue at C231 (P = 0.009);Gain of catalytic residue at C231 (P = 0.009);.;Gain of catalytic residue at C231 (P = 0.009);
MVP		1.0
MPC		0.95
ClinPred		1.0	D
GERP RS		-2.4
PromoterAI		-0.042	Neutral
Varity_R		0.99
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.24
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: rs121908035; hg19: chr19-11216275;