rs1202258257

Variant names:

• chr19-11120141-A-G
• rs1202258257
• NM_000527.5:c.1895A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-11120141-A-G
• chr19-11120141-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000527.5(LDLR):​c.1895A>G​(p.Asn632Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,784 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N632I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.31
• Publications: 2 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.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.869

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1895A>G	p.Asn632Ser	missense	Exon 13 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1895A>G	p.Asn632Ser	missense	Exon 13 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1772A>G	p.Asn591Ser	missense	Exon 12 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1895A>G	p.Asn632Ser	missense	Exon 13 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2153A>G	p.Asn718Ser	missense	Exon 13 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1895A>G	p.Asn632Ser	missense	Exon 13 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461784 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111908

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.3
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.021	D
Polyphen		0.59	P
Vest4		0.67
MutPred		0.61		Loss of stability (P = 0.117)
MVP		1.0
MPC		0.30
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.93
Mutation Taster		=17/83	disease causing

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: rs1202258257; hg19: chr19-11230817;