NM_000527.5:c.693C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000527.5(LDLR):​c.693C>T​(p.Cys231Cys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,194,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LDLR NM_000527.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.003740
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-11105599-C-T is Benign according to our data. Variant chr19-11105599-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2773501.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.693C>T	p.Cys231Cys	splice_region synonymous	Exon 4 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.693C>T	p.Cys231Cys	splice_region synonymous	Exon 4 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.570C>T	p.Cys190Cys	splice_region synonymous	Exon 3 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.693C>T	p.Cys231Cys	splice_region synonymous	Exon 4 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.951C>T	p.Cys317Cys	splice_region synonymous	Exon 4 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.693C>T	p.Cys231Cys	splice_region synonymous	Exon 4 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000754 AC: 9 AN: 1194076 Hom.: 0 Cov.: 33 AF XY: 0.00000668 AC XY: 4 AN XY: 598812

African (AFR) AF: 0.00 AC: 0 AN: 28076

American (AMR) AF: 0.00 AC: 0 AN: 42224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22422

East Asian (EAS) AF: 0.000243 AC: 8 AN: 32986

South Asian (SAS) AF: 0.00 AC: 0 AN: 81182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3962

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 891656

Other (OTH) AF: 0.0000203 AC: 1 AN: 49164

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Familial hypercholesterolemia (2)
-	-	1	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		-0.34
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0037
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.41		Position offset: -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;