NM_000527.5:c.409G>A

Variant names:

• chr19-11105315-G-A
• rs730882082
• NM_000527.5:c.409G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5

The NM_000527.5(LDLR):​c.409G>A​(p.Gly137Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,528 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001362900: "Another study has further corroborated these findings reporting this variant as conferring a high risk for familial hypercholesterolemia in 30% of Greenlanders (example, Jorsboe_2022). At least two publications report conflicting experimental evidence evaluating an impact on protein function. One study demonstrated the variant to confer no effect on LDL uptake (Thormaehlen_2015) while another study determined it caused a significant 61% reduction in LDL binding ability (Dube_2015)." PMID:22683370, 15823288, 25414273, 36267056, 33740630, 25647241" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137C) has been classified as Likely pathogenic. The gene LDLR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1 O:1
• Conservation: PhyloP100: 9.88
• Publications: 11 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001362900: "Another study has further corroborated these findings reporting this variant as conferring a high risk for familial hypercholesterolemia in 30% of Greenlanders (example, Jorsboe_2022). At least two publications report conflicting experimental evidence evaluating an impact on protein function. One study demonstrated the variant to confer no effect on LDL uptake (Thormaehlen_2015) while another study determined it caused a significant 61% reduction in LDL binding ability (Dube_2015)." PMID:22683370, 15823288, 25414273, 36267056, 33740630, 25647241; SCV005837068: Experimental studies have shown that this missense change affects LDLR function (PMID: 25414273).; SCV006063530: "In vitro functional studies using heterologous transfected cells have shown that this variant causes an intermediate reduction in LDL binding activity." PMID: 25414273; SCV004085589: An in vitro study showed this alteration had reduction in ligand binding compared to wild-type (Dubé JB et al. Circ Cardiovasc Genet, 2015 Feb;8:100-5).; SCV005344426: One functional study showed this variant caused 60% reduced ligand binding activity compared to wild-type (Dubé et al. 2015. PubMed ID: 25414273)
• PM1: In a hotspot region, there are 32 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 uncertain in NM_000527.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11105315-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 251207.
• 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, 0.979
• PP5: Variant 19-11105315-G-A is Pathogenic according to our data. Variant chr19-11105315-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 183087.

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.409G>A	p.Gly137Ser	missense	Exon 4 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.409G>A	p.Gly137Ser	missense	Exon 4 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.286G>A	p.Gly96Ser	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.409G>A	p.Gly137Ser	missense	Exon 4 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.667G>A	p.Gly223Ser	missense	Exon 4 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.409G>A	p.Gly137Ser	missense	Exon 4 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251184 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461528 Hom.: 1 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Familial hypercholesterolemia (3)
3	-	-	Hypercholesterolemia, familial, 1 (3)
1	1	-	not provided (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	LDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.79		Gain of phosphorylation at G137 (P = 0.0578)
MVP		1.0
MPC		0.78
ClinPred		0.98	D
GERP RS		5.4
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.60
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730882082; hg19: chr19-11215991;