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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.1069G>A (p.Glu357Lys)

CA10585290

251649 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: ccc16f7d-5c58-4e8c-ae15-1a7624c918e6
Approved on: 2023-04-28
Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.1069G>A
NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys)
NC_000019.10:g.11111522G>A
CM000681.2:g.11111522G>A
NC_000019.9:g.11222198G>A
CM000681.1:g.11222198G>A
NC_000019.8:g.11083198G>A
NG_009060.1:g.27142G>A
ENST00000558518.6:c.1069G>A
ENST00000252444.9:n.1323G>A
ENST00000455727.6:c.565G>A
ENST00000535915.5:c.946G>A
ENST00000545707.5:c.688G>A
ENST00000557933.5:c.1069G>A
ENST00000558013.5:c.1069G>A
ENST00000558518.5:c.1069G>A
ENST00000560173.1:n.68G>A
ENST00000560467.1:n.549G>A
NM_000527.4:c.1069G>A
NM_001195798.1:c.1069G>A
NM_001195799.1:c.946G>A
NM_001195800.1:c.565G>A
NM_001195803.1:c.688G>A
NM_001195798.2:c.1069G>A
NM_001195799.2:c.946G>A
NM_001195800.2:c.565G>A
NM_001195803.2:c.688G>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 5
PS4_Moderate PP4 PP3 PM3 PM2
Not Met criteria codes 21
PVS1 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PP1 PP2 BA1 PM1 PM4 PM5 PM6

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.1069G>A (p.Glu357Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS4_moderate, PP3 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID: 30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID: 19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines). PS4_moderate - Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID: 11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID: 28502510 (Bañares et al., 2017), Argentina). PP3 - REVEL = 0.976. PP4 - Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded.
Met criteria codes
PS4_Moderate
Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID: 11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID: 28502510 (Bañares et al., 2017), Argentina).
PP4
Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded.
PP3
REVEL = 0.976
PM3
Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID: 30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID: 19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines).
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
Not Met criteria codes
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
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.1069G>C (p.Glu357Gln) (ClinVar ID 431519) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.1070A>G (p.Glu357Gly) (ClinVar ID 251651) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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