19-11107506-A-G

Variant names:

• chr19-11107506-A-G
• rs761765254
• NM_000527.5:c.932A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM3 PM2 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.932A>G (p.Lys311Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (plasma cholesterol > 600mg/dL) and LDLR variant NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID: 251517), classified as Likely pathogenic by these guidelines, in trans (PMID:1301940), so PM3 is Met.PP4 - Variant meets PM2 and is identified in 1 index-case with SB/DLCN score of definite FH (plasma cholesterol > 600mg/dL with tendon xanthomas) from France (PMID:1301940), so PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585201/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:5 B:1
• Conservation: PhyloP100: 2.56
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.932A>G	p.Lys311Arg	missense	Exon 6 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.932A>G	p.Lys311Arg	missense	Exon 6 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.809A>G	p.Lys270Arg	missense	Exon 5 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.932A>G	p.Lys311Arg	missense	Exon 6 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1190A>G	p.Lys397Arg	missense	Exon 6 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.932A>G	p.Lys311Arg	missense	Exon 6 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456162 Hom.: 0 Cov.: 32 AF XY: 0.00000690 AC XY: 5 AN XY: 724384

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108284

Other (OTH) AF: 0.0000167 AC: 1 AN: 59968

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000778 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	1	Hypercholesterolemia, familial, 1 (4)
-	2	-	Familial hypercholesterolemia (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dyslipidemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.93	L
PhyloP100		2.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.58
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.84		Loss of ubiquitination at K311 (P = 0.013)
MVP		1.0
MPC		0.19
ClinPred		0.64	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.81
Mutation Taster		=4/96	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: rs761765254; hg19: chr19-11218182;