NM_000527.5:c.1773C>T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_000527.5(LDLR):c.1773C>T (p.Asn591Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 (★★).

• 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 ACMG Germline Pathogenicity v2019

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 -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (23/23 total B/LB).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4456 — exceeds 5%% threshold (BA1 applied)

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