rs750649426

Variant names:

• chr19-11111629-C-A
• rs750649426
• NM_000527.5:c.1176C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11111629-C-A
• chr19-11111629-C-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS4_Moderate PP1_Strong PM3 PM2 PVS1 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1176C>A (p.Cys392Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PP1_Strong, PM2, PM3, PS4_Moderate 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: PVS1 - variant is nonsense, causing a premature stop codon amino-terminal of amino acid 830 (NM_000527.5:p.Lys830), so PVS1 is met.PP1_strong - variant segregates with FH phenotype in:- 7 informative meiosis from 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge: 4 relatives positive for variant with LDL-C >75th percentile, and 3 relatives negative for variant with LDL-C <50th percentile.- 1 informative meiosis from 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 1 relative positive for variant with LDL-C >75th percentile.- 11 informative meiosis from 1 family from PMID:8831933 (Langenhoven et al. 1996): 11 relatives are positive for the variant and have LDL-C >75th percentile (9 have >5.0mmol, 2 have 4.6 and 4.3mmol)Segregation was observed in 19 informative meiosis from 3 families, so PP1_Strong is met.PM2 - PopMax MAF = 0.00003267 (0.003%) in South asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PM3 - variant meets PM2 and was identified in 1 index case who also carries NM_000527.5(LDLR):c.1A>T (p.Met1Leu), confirmed in trans, who has LDL 17.3mmol/L from PMID:8831933 (Langenhoven et al. 1996 Aug 23;125(1):111-9. --- 2nd variant is classified as Pathogenic with these guidelines, so PM3 is met.PS4_moderate - variant meets PM2 and was identified in:- 1 index case who fulfills Simon-Broome criteria of possible FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, Portugal;- 1 index case with DLCN>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France;- 4 unrelated index cases, all with Dutch lipid clinic network >=6, from Robarts Research Institute, Canada;- 1 Index case (iii-4) with DLCN at least 8 (LDL-C 17.3mmol at 4yo with tendon xanthoma) from PMID:8831933 (Langenhoven et al. 1996), South Africa; - 1 index case with heterozygous FH per MEDPED criteria from PMID:11933210 (Salazar et al. 2002), Brazil;- at least 1 index case with definite FH ("definite heterozygous FH by cardiologists and internists using a uniform protocol and internationally accepted criteria [Defesche, 2000].") from PMID 11810272 (Fouchier et al. 2001), The Netherlands.9 unrelated cases, so PS4_Moderate is met.PP4 - variant meets PM2 and was identified in 9 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA032391/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LDLR ENST00000558518.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 4.02
• Publications: 3 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: Pathogenic. The variant received 19 ACMG points.

• PVS1: 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.
• PM3: 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: ENST00000558518.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1176C>A	p.Cys392*	stop_gained	Exon 8 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1176C>A	p.Cys392*	stop_gained	Exon 8 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1053C>A	p.Cys351*	stop_gained	Exon 7 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1176C>A	p.Cys392*	stop_gained	Exon 8 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1434C>A	p.Cys478*	stop_gained	Exon 8 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1176C>A	p.Cys392*	stop_gained	Exon 8 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250606 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 1461182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726890

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111850

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000396 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Hypercholesterolemia, familial, 1 (8)
2	-	-	Familial hypercholesterolemia (2)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		4.0
Vest4		0.94
GERP RS		3.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs750649426; hg19: chr19-11222305;