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]

Variant: NM_000527.5(LDLR):c.226G>C (p.Gly76Arg)

CA042515

1331775 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 4020be23-0433-4d1e-9d5b-828c68b7d8f4
Approved on: 2023-04-28
Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.226G>C
NM_000527.5(LDLR):c.226G>C (p.Gly76Arg)
NC_000019.10:g.11102699G>C
CM000681.2:g.11102699G>C
NC_000019.9:g.11213375G>C
CM000681.1:g.11213375G>C
NC_000019.8:g.11074375G>C
NG_009060.1:g.18319G>C
ENST00000558518.6:c.226G>C
ENST00000252444.9:n.480G>C
ENST00000455727.6:c.226G>C
ENST00000535915.5:c.190+2354G>C
ENST00000545707.5:c.226G>C
ENST00000557933.5:c.226G>C
ENST00000557958.1:n.312G>C
ENST00000558013.5:c.226G>C
ENST00000558518.5:c.226G>C
NM_000527.4:c.226G>C
NM_001195798.1:c.226G>C
NM_001195799.1:c.190+2354G>C
NM_001195800.1:c.226G>C
NM_001195803.1:c.226G>C
NM_001195798.2:c.226G>C
NM_001195799.2:c.190+2354G>C
NM_001195800.2:c.226G>C
NM_001195803.2:c.226G>C
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Uncertain Significance

Met criteria codes 2
PS3_Moderate PP3
Not Met criteria codes 19
BS4 BS3 BS1 BS2 BP2 BP3 BP4 PS2 PS4 PS1 BA1 PP1 PP4 PM6 PM2 PM3 PM1 PM4 PM5

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.226G>C (p.Gly76Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS3_Moderate and PP3 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: PS3_Moderate: Level 2 assays: PMID 34970301: Heterologous cells (HEK-293), WB and CLSM assays - result: 63% uptake. Result it below 70% of wild-type, so PS3_Moderate is met. PP3: REVEL=0.83. It is above 0.75. So, PP3 is met.
Met criteria codes
PS3_Moderate
Level 2 assays: PMID 34970301: Heterologous cells (HEK-293), WB and CLSM assays - result: 63% uptake. Result it below 70% of wild-type, so PS3_Moderate is met.
PP3
REVEL=0.83. It is above 0.75. So, PP3 is met.
Not Met criteria codes
BS4
No data available.
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
FAF= 0.0001062 (0.01062%)
BS2
No data available.
BP2
No data available.
BP3
No in-frame deletions/insertions
BP4
REVEL=0.83. It is above 0.5.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant doesn't meet PM2.
PS1
No other missense variant in the codon with the same amino acid change.
BA1
FAF= 0.0001062 (0.01062%)
PP1
No data available.
PP4
Variant doesn't meet PM2.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
PopMax MAF= 0.00027 (0.027%) in East Asian exomes+genomes (gnomAD v2.1.1).
PM3
No data available.
PM1
Not on exon 4. Not a cysteine residue.
PM4
No in-frame deletions/insertions
PM5
One other missense variant in the same codon: NM_000527.5(LDLR):c.226G>T (p.Gly76Trp) (ClinVar ID 251081) Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines
Curation History
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