rs387906303

Variant names:

• chr19-11105576-G-A
• rs387906303
• NM_000527.5:c.670G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11105576-G-A
• chr19-11105576-G-C

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.670G>A​(p.Asp224Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,426 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004829274: Functional studies suggest that this variant results in a deleterious effect on the protein (PMID:30617148, 29874871, 1301956).; SCV006063532: "Functional studies using transfected HEK293 cells have shown that this variant causes a decrease in LDL uptake (PMID:30617148). Another functional study using cultured fibroblasts derived from a homozygous individual affected with familial hypercholesteremia have shown that this variant causes a significant reduction in LDL receptor activity (PMID:1301956)."; SCV002664572: Functional studies suggest this alteration causes reduced LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Deng SJ et al. J. Lipid Res., 2019 Jan;epub ahead of print).; SCV006562261: Published functional studies suggest on p.(D224N) fibroblasts cultures show that the variant has a <2% degradation activity compared to the wild-type, suggesting the variant enzymatic activity is severely affected (PMID:1301956)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D224E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.88
• Publications: 13 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

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004829274: Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 30617148, 29874871, 1301956).; SCV006063532: "Functional studies using transfected HEK293 cells have shown that this variant causes a decrease in LDL uptake (PMID: 30617148). Another functional study using cultured fibroblasts derived from a homozygous individual affected with familial hypercholesteremia have shown that this variant causes a significant reduction in LDL receptor activity (PMID: 1301956)."; SCV002664572: Functional studies suggest this alteration causes reduced LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Deng SJ et al. J. Lipid Res., 2019 Jan;epub ahead of print).; SCV006562261: Published functional studies suggest on p.(D224N) fibroblasts cultures show that the variant has a <2% degradation activity compared to the wild-type, suggesting the variant enzymatic activity is severely affected (PMID: 1301956)
• PM1: In a hotspot region, there are 40 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11105578-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375790.
• 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, 0.989
• PP5: Variant 19-11105576-G-A is Pathogenic according to our data. Variant chr19-11105576-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.670G>A	p.Asp224Asn	missense	Exon 4 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.670G>A	p.Asp224Asn	missense	Exon 4 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.547G>A	p.Asp183Asn	missense	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.670G>A	p.Asp224Asn	missense	Exon 4 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.928G>A	p.Asp310Asn	missense	Exon 4 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.670G>A	p.Asp224Asn	missense	Exon 4 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454426 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 722792

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108072

Other (OTH) AF: 0.00 AC: 0 AN: 60000

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.96		Loss of phosphorylation at S226 (P = 0.0983)
MVP		1.0
MPC		0.79
ClinPred		0.99	D
GERP RS		5.6
PromoterAI		0.0049	Neutral
Varity_R		0.86
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs387906303; hg19: chr19-11216252;