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]
Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.241C>T (p.Arg81Cys)

CA023666

183083 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 91b21a4d-b55d-40a8-ab5f-5bacc76d8762

HGVS expressions

NM_000527.5:c.241C>T
NM_000527.5(LDLR):c.241C>T (p.Arg81Cys)
NC_000019.10:g.11102714C>T
CM000681.2:g.11102714C>T
NC_000019.9:g.11213390C>T
CM000681.1:g.11213390C>T
NC_000019.8:g.11074390C>T
NG_009060.1:g.18334C>T
ENST00000558518.6:c.241C>T
ENST00000252444.9:n.495C>T
ENST00000455727.6:c.241C>T
ENST00000535915.5:c.190+2369C>T
ENST00000545707.5:c.241C>T
ENST00000557933.5:c.241C>T
ENST00000557958.1:n.327C>T
ENST00000558013.5:c.241C>T
ENST00000558518.5:c.241C>T
NM_000527.4:c.241C>T
NM_001195798.1:c.241C>T
NM_001195799.1:c.190+2369C>T
NM_001195800.1:c.241C>T
NM_001195803.1:c.241C>T
NM_001195798.2:c.241C>T
NM_001195799.2:c.190+2369C>T
NM_001195800.2:c.241C>T
NM_001195803.2:c.241C>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 5
PP4 PP3 PM2 PS4_Supporting PS3_Supporting
Not Met criteria codes 21
PS2 PS1 PP1 PP2 BA1 PM6 PM3 PM1 PM4 PM5 PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.241C>T (p.Arg81Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP3, PS4_supporting, and PS3_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 MAF = 0.00001758 (0.001758%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.817 PP4 - Variant meets PM2 and is identified 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PS3_supporting - Level 3 assay: PMID 25647241. HeLa cells, alternative microscopy assay, results - LDL-uptake 68%. PS4_supporting - Variant meets PM2 and is identified in 5 index cases (2 cases with DLCN criteria>=6 from in PMID: 33418990 (Meshkov et al., 2021); at least 1 case with DLCN definite in PMID: 11810272 (Fouchier et al., 2001); 1 case with DLCN definite in PMID: 9712531 (Nissen et al., 1998); 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
Met criteria codes
PP4
Variant meets PM2 and is identified 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
PP3
REVEL = 0.817
PM2
PopMax MAF = 0.00001758 (0.001758%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1)
PS4_Supporting
Variant meets PM2 and is identified in 5 index cases (2 cases with DLCN criteria>=6 from in PMID: 33418990 (Meshkov et al., 2021); at least 1 case with DLCN definite in PMID: 11810272 (Fouchier et al., 2001); 1 case with DLCN definite in PMID: 9712531 (Nissen et al., 1998); 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).
PS3_Supporting
Level 3 assay: PMID 25647241. HeLa cells, alternative microscopy assay, results - LDL-uptake 68%.
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Only 1 documented case of segregation from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 other missense variants in the same codon: - NM_000527.5(LDLR):c.242G>A (p.Arg81His)(ClinVar ID 924271) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.241C>A (p.Arg81Ser)(ClinVar ID 251088) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2023-04-28
Published on: 2023-05-01
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