Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)

CA023567

200921 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: de63ac3f-3eb4-4eeb-bdc2-12f22ab90103
Approved on: 2023-11-07
Published on: 2024-12-24

HGVS expressions

NM_000527.5:c.1747C>T
NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)
NC_000019.10:g.11116900C>T
CM000681.2:g.11116900C>T
NC_000019.9:g.11227576C>T
CM000681.1:g.11227576C>T
NC_000019.8:g.11088576C>T
NG_009060.1:g.32520C>T
ENST00000252444.10:c.2005C>T
ENST00000559340.2:c.1705+688C>T
ENST00000560467.2:c.1627C>T
ENST00000558518.6:c.1747C>T
ENST00000252444.9:c.2001C>T
ENST00000455727.6:c.1243C>T
ENST00000535915.5:c.1624C>T
ENST00000545707.5:c.1366C>T
ENST00000557933.5:c.1747C>T
ENST00000558013.5:c.1747C>T
ENST00000558518.5:c.1747C>T
ENST00000559340.1:c.426+688C>T
NM_000527.4:c.1747C>T
NM_001195798.1:c.1747C>T
NM_001195799.1:c.1624C>T
NM_001195800.1:c.1243C>T
NM_001195803.1:c.1366C>T
NM_001195798.2:c.1747C>T
NM_001195799.2:c.1624C>T
NM_001195800.2:c.1243C>T
NM_001195803.2:c.1366C>T
More

Pathogenic

Met criteria codes 7
PS4 PS3 PP4 PP3 PM2 PM3 PP1_Strong
Not Met criteria codes 16
BP7 BP5 BP3 BP4 BP1 PS2 PS1 PP2 PVS1 PM6 PM1 PM4 PM5 BA1 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PS4, PP1_Strong, PM2, PM3, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.001203 (0.12%) in East Asian (gnomAD v2.1.1). PopMax MAF > 0.02% (PM2 is "not met"), however, after reviewing literature cases, a founder effect - mostly Asian ancestry - seems to be associated (PMID 27206935 - Chiou et al. 2016; several case reports used for PS4). This variant was also found in other populations: PopMax MAF = 0.016% in South Asian (gnomAD v2.1.1). PP3: REVEL = 0.884. PS3: Functional studies reported in PMID 32695144 (Dušková et al., 2020) performed using heterologous cells (CHO), WB and FACS - results - 52% expression and 44% internalization. The variant showed a deleterious effect on the protein localization and function, and was associated with the accumulation of the protein in the ER. Results are below 70%, so PS3 is met. // Functional studies reported in PMID 21511053 (Zhao et al., 2011) performed using retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays - results - approximately 50% cell surface LDLR, 50-60% LDL-LDLR uptake and normal LDL-LDLR binding. Results are below 70%, so PS3 is met. -------- Overall, both functional studies are consistent with damaging effect. PS4, PP4: Variant meets PM2 and is identified in at least 17 unrelated index cases fulfilling criteria for FH (2 index cases 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; at least 15 cases from PMID 20538126, 22353362, 21376320, 25846081, 19318025). PP1_Strong: Variant segregates with FH phenotype in at least 9 informative meioses (minimum 6) from 3 families from different PMIDs (23155708, 2923363, 22353362): 9 affected family members have the variant. PM3: Variant meets PM2 and is identified in 1 index case (PMID 7903864) with homozygous FH phenotype and a deletion of LDLR exons 4-11, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 23155708) with homozygous FH phenotype and the LDLR c.2054C>T, p.(Pro685Leu) variant, confirmed in trans, classified as Pathogenic by these guidelines; 1 index case (PMID 29233637) with homozygous FH phenotype and the LDLR c.724C>T, p.(Gln242*) variant, confirmed in trans, classified as Pathogenic by these guidelines.
Met criteria codes
PS4
Variant meets PM2 and was identified in 17 unrelated index cases - 2 index cases (one fullfiling SB criteria and one with clinical DLCN ≥ 6 after alternative causes of high cholesterol were excluded, both from Centre de Génétique Moléculaire et Chromosomique, Hôpital de la Pitié-Salpêtrière) // (5+1+7+1) 14 index cases fullfling SB criteria for FH, after alternative causes of high cholesterol are excluded (PMID:20538126, 22353362, 21376320, 25846081) // at least 1 index case (PMID:19318025) with the variant and DLCN criteria≥ 6.
PS3
Functional studies (PMID: 32695144) performed using Heterologous cells (CHO), WB and FACS - results - 52% expression and 44% internalisation. The variant showed a deleterious effect on the protein localization and function, and was associated with the accumulation of the protein on ER. Results are below 70%, so PS3 is met. // Functional studies (PMID: 21511053) performed using retrovirus transfected LDLR-/- fibroblasts, FACS and 125I-LDL assays - results - approximately 50% cell surface LDLR, 50-60% LDL-LDLR uptake and normal LDL-LDLR binding. Results are below 70%, so PS3 is met. -------- Overall, both functional studies are consistent with damaging effect. (not considered): Funtional studies (PMID: 7903864) performed using heterologous cells (COS), immunoblot - results - approximately 50% mature protein and binds LDL. No specific information regarding % activity, binding or uptake. Therefore this study was not considered towards PS3.
PP4
Variant meets PM2 and was Identified in 1 FH case fullfiling SB criteria and 1 FH case with clinical Dutch Lipid Clinic Network Criteria score ≥ 6 after alternative causes of high cholesterol were excluded, both from Centre de Génétique Moléculaire et Chromosomique (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).
PP3
REVEL = 0.884. It is above 0.75, so PP3 is met.
PM2
PopMax MAF = 0.001203 (0.12%) in East Asian (gnomAD v2.1.1). PopMax MAF > 0.02% (PM2 "is not met"), however, after reviewing literature cases, a founder effect - mostly asian ancestry - seems to be associated (PMID:27206935 and several case reports used for PS4). This variant was also found in other populations: PopMax MAF = 0.016% in South Asian (gnomAD v2.1.1).
PM3
Variant was identified in 1 CpHtz index case (PMID:7903864) with homozygous FH phenotype (TC 15.76 nmol/L and LDL 14 nmol/L, xanthomas) presenting, in trans, the deletion of LDLR exons 4-11, classified as Pathogenic by these guidelines // 1 CpHtz index case (PMID:23155708) with homozygous FH phenotype (TC 13.95 nmol/L and LDL11.25 nmol/L, xanthomata) presenting, in trans, the variant c.2054C>T/p.(Pro685Leu) in the LDLR, classified as Pathogenic by these guidelines // 1 CpHtz index case (PMID:29233637) with homozygous FH phenotype (TC 785 mg/dL and LDL 575mg/dL, xanthomas) presenting, in trans, the variant c.724C>T/p.(Gln242*) in the LDLR, classified as Pathogenic by these guidelines.
PP1_Strong
Variant segregates with FH phenotype in 9 informative meioses (minimum 6) from 3 families from different PMIDs: (F1) two relatives of a CpHtz FH patien from PMID:23155708: father (TC 7.7 nmol/L and LDL-c 4.9 nmol/L) and grandmother (TC 11.2 nmol/L and LDL-c 7.61 nmol/L) who were htz for the variant under curation // (F2) two relatives of a CpHtz FH patien from PMID:29233637: mother (LDL-c 231 mg/dL) and grandfather (LDL-c 229 mg/dL) who were htz for the variant under curation // (F3) five relatives of a Htz patient from PMID: 22353362 positives for the variant and with LDL-C>75th percentile. (one family) only one relative (father) from PMID:7903864 of a CpHtz FH patient, who was htz for the variant under curation (TC of 4.9 nmol/L and LDL-c of 2.97 nmol/L)
Not Met criteria codes
BP7
Variant is not synonymous and does not met BP4.
BP5
N/A according to FHVCEP guidelines
BP3
N/A according to FHVCEP guidelines
BP4
REVEL = 0.884. It not under 0.50, so BP4 is not met.
BP1
N/A according to FHVCEP guidelines
PS2
No de novo cases identified
PS1
No other variant giving same amino acid change identified
PP2
N/A according to FHVCEP guidelines
PVS1
The variant is missense, therefore PVS1 is not applied
PM6
No de novo cases identified
PM1
Variant in exon 12 of the LDLR gene (not located at exon 4)
PM4
The variant is missense, therefore PM4 is not applied
PM5
Other variants identified, but none are pathogenic
BA1
BA1 / BS1: FAF = 0.0008091 (0.0809%) in gnomAD v2.1.1. The FAF is not above 0.5%, so BA1 not met; and is not between 0.2-0.5%, so BS1 is not met.
BS3
Not met, no reports
BS1
BA1 / BS1: FAF = 0.0008091 (0.0809%) in gnomAD v2.1.1. The FAF is not above 0.5%, so BA1 not met; and is not between 0.2-0.5%, so BS1 is not met.
Curation History
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