19-11106676-G-A

Variant names:

• chr19-11106676-G-A
• rs143992984
• NM_000527.5:c.806G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP1_Moderate BS2 BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.806G>A (p.Gly269Asp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BP2 and PP1_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS2 - Identified in 7 heterozygous controls from ABraOM database, and 2 non-affected family members from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 - variant identified in 2 Index cases with heterozygous FH phenotype and a 2nd LDLR variant classified as Pathogenic by these guidelines.PP1_moderate - variant segregates with phenotype in 5 informative meiosis in 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023767/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign reviewed by expert panel P:2 U:3 B:14 O:1
• Conservation: PhyloP100: 2.44
• Publications: 15 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: Likely_benign. The variant received -3 ACMG points.

• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.806G>A	p.Gly269Asp	missense	Exon 5 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.806G>A	p.Gly269Asp	missense	Exon 5 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.683G>A	p.Gly228Asp	missense	Exon 4 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.806G>A	p.Gly269Asp	missense	Exon 5 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1064G>A	p.Gly355Asp	missense	Exon 5 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.806G>A	p.Gly269Asp	missense	Exon 5 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 251476 AF XY: 0.000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000164 AC: 240 AN: 1461856 Hom.: 1 Cov.: 31 AF XY: 0.000169 AC XY: 123 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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: 0.000145 AC: 161 AN: 1111980

Other (OTH) AF: 0.000348 AC: 21 AN: 60396

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74476

African (AFR) AF: 0.000120 AC: 5 AN: 41586

American (AMR) AF: 0.00144 AC: 22 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000191 Hom.: 1

Bravo AF: 0.000404

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	8	Hypercholesterolemia, familial, 1 (11)
-	-	3	Familial hypercholesterolemia (3)
-	1	1	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypercholesterolemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	-0.31	N
PhyloP100		2.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.66
Sift	Benign	0.33	T
Sift4G	Benign	0.29	T
Polyphen		0.0090	B
Vest4		0.50
MVP		1.0
MPC		0.40
ClinPred		0.088	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.57
gMVP		0.87
Mutation Taster		=1/99	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: rs143992984; hg19: chr19-11217352;