rs875989936

Variant names:

• chr19-11120201-T-C
• rs875989936
• NM_000527.5:c.1955T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP1_Strong PM2 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and PS4_Supporting 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: PopMax = 0.00005 in East Asians (gnomAD v2.1.1).PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases who fulfil clinical criteria for FH: 1 patient with DLCN >6 from the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI); 1 patient with Simon Broome = Definite FH (PMID:20236128).PP1_Strong: Variant segregates with the FH phenotype in 8 informative meioses from 1 family from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA, Australia; VCI): 5 affected family members have the variant and 3 non-affected family members do not have the variant.PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills clinical criteria for FH (Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA, Australia; VCI), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576326/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:2
• Conservation: PhyloP100: 7.85
• Publications: 9 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 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.1955T>C	p.Met652Thr	missense	Exon 13 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1955T>C	p.Met652Thr	missense	Exon 13 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1832T>C	p.Met611Thr	missense	Exon 12 of 17	NP_001182728.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1955T>C	p.Met652Thr	missense	Exon 13 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2213T>C	p.Met738Thr	missense	Exon 13 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1955T>C	p.Met652Thr	missense	Exon 13 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

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: 0.00 AC: 0 AN: 1111976

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	1	-	Hypercholesterolemia, familial, 1 (5)
2	1	-	Familial hypercholesterolemia (3)
1	-	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Benign	0.87
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.55	N
PhyloP100		7.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0060	B
Vest4		0.38
MutPred		0.68		Gain of sheet (P = 0.0827)
MVP		1.0
MPC		0.59
ClinPred		0.63	D
GERP RS		4.3
Varity_R		0.70
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs875989936; hg19: chr19-11230877;