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]
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Variant: NM_000527.5(LDLR):c.190+4A>T

CA042227

225097 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: c7021a50-713d-4798-bd35-cce7eb2c158d

HGVS expressions

NM_000527.5:c.190+4A>T
NM_000527.5(LDLR):c.190+4A>T
NC_000019.10:g.11100349A>T
CM000681.2:g.11100349A>T
NC_000019.9:g.11211025A>T
CM000681.1:g.11211025A>T
NC_000019.8:g.11072025A>T
NG_009060.1:g.15969A>T
ENST00000558518.6:c.190+4A>T
ENST00000252444.9:n.444+4A>T
ENST00000455727.6:c.190+4A>T
ENST00000535915.5:c.190+4A>T
ENST00000545707.5:c.190+4A>T
ENST00000557933.5:c.190+4A>T
ENST00000557958.1:n.276+4A>T
ENST00000558013.5:c.190+4A>T
ENST00000558518.5:c.190+4A>T
ENST00000560502.5:n.280A>T
NM_000527.4:c.190+4A>T
NM_001195798.1:c.190+4A>T
NM_001195799.1:c.190+4A>T
NM_001195800.1:c.190+4A>T
NM_001195803.1:c.190+4A>T
NM_001195798.2:c.190+4A>T
NM_001195799.2:c.190+4A>T
NM_001195800.2:c.190+4A>T
NM_001195803.2:c.190+4A>T

Likely Pathogenic

Met criteria codes 4
PS4 PM2 PS3_Moderate PP4
Not Met criteria codes 21
PS2 PS1 PM6 PM3 PM1 PM4 PM5 BA1 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 PP1 PP3 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.190+4A>T variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4 and PS3_Moderate) 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 = 0.00020 (0.02%) in East Asian exomes+genomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Variant identified in 11 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 21418584; 3 cases fulfilling Simon-Broome criteria published in PMID: 20236128; 5 cases with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 1 case with Dutch lipid clinic network >=6 from Robarts Research Institute; 1 case with MedPed definite from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory. PS3_Moderate - Level 2 assays: PMID 19208450: Heterozygous patient cells, FACS/RT-PCR/Nothern blotting assays - result - 47% low-density lipoprotein particle receptor activity (LDLR activity reported as a mean value of cell-surface LDLR and LDL internalization measurements); aberrant transcript is not confirmed by sequencing (NMD expected) and is 40% of total transcripts. PS4 - Variant meets PM2. Variant identified in 11 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 21418584; 3 cases fulfilling Simon-Broome criteria published in PMID: 20236128; 5 cases with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 1 case with Dutch lipid clinic network >=6 from Robarts Research Institute; 1 case with MedPed definite from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory.
Met criteria codes
PS4
Variant meets PM2. Variant identified in 11 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 21418584; 3 cases fulfilling Simon-Broome criteria published in PMID: 20236128; 5 cases with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 1 case with Dutch lipid clinic network >=6 from Robarts Research Institute; 1 case with MedPed definite from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory.
PM2
PopMax MAF = 0.00020 (0.02%) in East Asian exomes+genomes (gnomAD v2.1.1).
PS3_Moderate
Level 2 assays: PMID 19208450: Heterozygous patient cells, FACS/RT-PCR/Nothern blotting assays - result - 47% low-density lipoprotein particle receptor activity (LDLR activity reported as a mean value of cell-surface LDLR and LDL internalization measurements); aberrant transcript is not confirmed by sequencing (NMD expected) and is 40% of total transcripts.
PP4
Variant meets PM2. Variant identified in 11 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 21418584; 3 cases fulfilling Simon-Broome criteria published in PMID: 20236128; 5 cases with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 1 case with Dutch lipid clinic network >=6 from Robarts Research Institute; 1 case with MedPed definite from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory.
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
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
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
PVS1
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
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
Functional data available.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-02-09
Published on: 2022-07-12
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