rs749038326

Variant names:

• chr19-11102741-G-A
• rs749038326
• NM_000527.5:c.268G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11102741-G-A
• chr19-11102741-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM5_Strong PS4_Moderate PP1_Moderate PM2 PP4 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP1_Moderate, PS3_Moderate, PS4_Moderate and PP4 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: PM5_strong - there are 4 other missense variants is the same codon:- NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines- NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelines- NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines--- There are 2 variants classified as Pathogenic, so PM5_Strong is met.PP1_moderate - Variant segregates with phenotype in 4 informative meiosis from different labs: - 1 unaffected family member does not have the variant, from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation);- 3 informative meiosis from 1 family from PMID 12837857 (Chang et al. 2003): 1 relative has the variant and phenotype (III:1), plus 2 relatives do not have the variant and do not have the phenotype (II:1 and III:2)4 informative meiosis, so PP1_Moderate is met.PM2 - PopMax MAF = 0.0008019 (0.08019%) in East Asian (gnomAD v2.1.1), but this is a founder variant in East Asian populations, so PM2 can be met in this instance.PS3_moderate - Level 2 FS: Chang et al., 2003 (PMID:12837857): Heterologous cells (COS-7), FACS assays - results: 55% LDLR cell surface and uptake. Binding is not studied, so not all cycle is studied (level 2 and not level 1)---- functional study is consistent with damaging effect, activity is below 70% of wild-type, so PS3_Moderate is met.PS4_moderate - variant meets PM2 and was identified in:- 1 index case who fulfills Simon Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic;- 3 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada;- at least 1 index case with DLCN score of definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583645.1 in ClinVar), France;- 1 index case who fulfills SB criteria of at least possible FH from PMID 9259195 (Day et al., 1997), UK;- 1 index case who fulfills SB criteria of at least possible FH from PMID 25962062 (Han et al., 2015), Korea;- 2 unrelated index cases who fulfill SB criteria of possible FH (TC>8mmol/L, plus CAD) from PMID 12837857 (Chang et al., 2003), Taiwan, China;9 cases, so PS4_Moderate is met.PP4 - variant meets PM2 and was identified in 9 unrelated index cases from different labs (see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA042604/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:25 B:1
• Conservation: PhyloP100: 9.95
• Publications: 29 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 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.268G>A	p.Asp90Asn	missense	Exon 3 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.268G>A	p.Asp90Asn	missense	Exon 3 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195800.2		c.268G>A	p.Asp90Asn	missense	Exon 3 of 16	NP_001182729.1	P01130-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.268G>A	p.Asp90Asn	missense	Exon 3 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.526G>A	p.Asp176Asn	missense	Exon 3 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.268G>A	p.Asp90Asn	missense	Exon 3 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251486 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39686

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

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

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111900

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000694 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
13	-	1	Hypercholesterolemia, familial, 1 (14)
7	-	-	not provided (7)
3	-	-	Familial hypercholesterolemia (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Homozygous familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.9
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.92		Gain of MoRF binding (P = 0.0707)
MVP		1.0
MPC		0.80
ClinPred		0.48	T
GERP RS		5.7
Varity_R		0.95
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: rs749038326; hg19: chr19-11213417; COSMIC: COSV99370378; COSMIC: COSV99370378;