rs688

Variant names:

• chr19-11116926-C-T
• rs688
• NM_000527.5:c.1773C>T
• LDLR p.Asn591Asn

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB4_Strong

The NM_000527.5(LDLR):c.1773C>T (p.Asn591Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The gene LDLR is a known oncogene (CancerMine: 2 oncogene citations). The variant allele was found at a cumulative frequency of 0.417 (AC=673,211) in the gnomAD database across 1,613,584 control chromosomes, including 147,093 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.446. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.).

• Frequency:
  • Genomes: 𝑓 0.34 (10427 hom., cov: 31)
  • Exomes 𝑓: 0.43 (136666 hom.)
• Consequence: LDLR NM_000527.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -4.22
• Publications: 1 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: SD, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Natera
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.446 — exceeds 1% threshold (B1 applied)
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LDLR NM_000527.5	MANE Select	c.1773C>T p.Asn591Asn	synonymous	Exon 12 of 18	Prot: NP_000518.1 UniProt:
	LDLR NM_001195798.2		c.1773C>T p.Asn591Asn	synonymous	Exon 12 of 18	Prot: NP_001182727.1 UniProt:
	LDLR NM_001195799.2		c.1650C>T p.Asn550Asn	synonymous	Exon 11 of 17	Prot: NP_001182728.1 UniProt:

LDLR NM_000527.5

MANE Select

HGVSc / HGVSpc.1773C>Tp.Asn591Asn

Exon rankExon 12 of 18

synonymous

Prot: NP_000518.1UniProt: P01130-1

LDLR NM_001195798.2

HGVSc / HGVSpc.1773C>Tp.Asn591Asn

Exon rankExon 12 of 18

synonymous

Prot: NP_001182727.1UniProt: P01130-5

LDLR NM_001195799.2

HGVSc / HGVSpc.1650C>Tp.Asn550Asn

Exon rankExon 11 of 17

synonymous

Prot: NP_001182728.1UniProt: P01130-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LDLR ENST00000558518.6	TSL:1MANE Select	c.1773C>T p.Asn591Asn	synonymous	Exon 12 of 18	Prot: ENSP00000454071.1 UniProt:
	LDLR ENST00000252444.10	TSL:1	c.2031C>T p.Asn677Asn	synonymous	Exon 12 of 18	Prot: ENSP00000252444.6 UniProt:
	LDLR ENST00000558013.5	TSL:1	c.1773C>T p.Asn591Asn	synonymous	Exon 12 of 18	Prot: ENSP00000453346.1 UniProt:

LDLR ENST00000558518.6

TSL:1MANE Select

HGVSc / HGVSpc.1773C>Tp.Asn591Asn

Exon rankExon 12 of 18

synonymous

Prot: ENSP00000454071.1UniProt: P01130-1

LDLR ENST00000252444.10

TSL:1

HGVSc / HGVSpc.2031C>Tp.Asn677Asn

Exon rankExon 12 of 18

synonymous

Prot: ENSP00000252444.6UniProt: J3KMZ9

LDLR ENST00000558013.5

TSL:1

HGVSc / HGVSpc.1773C>Tp.Asn591Asn

Exon rankExon 12 of 18

synonymous

Prot: ENSP00000453346.1UniProt: P01130-5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.337	AC:51230	Hom:10439	AN:151818	Cov:31
GnomAD2 exomes	AF: 0.389	AC:97866	Hom:	AN:251472	Cov:
GnomAD4 exome	AF: 0.426	AC:622001	Hom:136666	AN:1461646	Cov:43
GnomAD4 genome	AF: 0.337	AC:51210	Hom:10427	AN:151938	Cov:31
TOPMed (Bravo)	AF: 0.321	AC:84921	Hom:16478	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.400	AC:182117	Hom:38700	AN:455066	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.355	AC:832	Hom:162	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.167	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.420	AC:126	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.335	AC:4360	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.266	AC:923	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.144	AC:1040	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.481	AC:965	Hom:	AN:2008	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.121	AC:14833	Hom:951	AN:122156	Cov:
Turkish Variome	AF: 0.407	AC:2735	Hom:591	AN:6718	Cov:
UK10K	AF: 0.449	AC:3392	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.170	AC:1524	Hom:133	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.414 *	4592	11098	0.411 *	7244	17604
BipEx(Bipolar disorder (including schizoaffective))	0.438	12447	28420	0.438	12635	28844
Epi25(Epilepsy)	0.389	16330	41956	0.406	27121	66882
SCHEMA(Schizophrenia)	0.312	41202	131958	0.329	69948	212874

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	Hypercholesterolemia, familial, 1 (9)
-	-	7	not specified (7)
-	-	4	Familial hypercholesterolemia (4)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.00076
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.092
DANN	Benign	0.70
GPN-Star LLR	N/A	-0.71
GPN-Star score	N/A	0.45
Mutation Taster	N/A	98/2	polymorphism (auto)
PhyloP100	Benign	-4.2
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs688;

hg19: chr19-11227602;

COSMIC: COSV52942945;

COSMIC: COSV52942945;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar