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Variant: NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys)

CA404082719

1395739 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: f40ccd74-b0bc-4f96-bbe1-ad5342f0c802
Approved on: 2023-04-28
Published on: 2023-05-01

HGVS expressions

NM_000527.5:c.1003G>T
NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys)
NC_000019.10:g.11110714G>T
CM000681.2:g.11110714G>T
NC_000019.9:g.11221390G>T
CM000681.1:g.11221390G>T
NC_000019.8:g.11082390G>T
NG_009060.1:g.26334G>T
ENST00000558518.6:c.1003G>T
ENST00000252444.9:n.1257G>T
ENST00000455727.6:c.499G>T
ENST00000535915.5:c.880G>T
ENST00000545707.5:c.622G>T
ENST00000557933.5:c.1003G>T
ENST00000558013.5:c.1003G>T
ENST00000558518.5:c.1003G>T
ENST00000560173.1:n.2G>T
ENST00000560467.1:n.541-800G>T
NM_000527.4:c.1003G>T
NM_001195798.1:c.1003G>T
NM_001195799.1:c.880G>T
NM_001195800.1:c.499G>T
NM_001195803.1:c.622G>T
NM_001195798.2:c.1003G>T
NM_001195799.2:c.880G>T
NM_001195800.2:c.499G>T
NM_001195803.2:c.622G>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PM2 PS3_Moderate PP4 PP3
Not Met criteria codes 22
PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PVS1 PS2 PS4 PS1 BA1 PP1 PP2

Evidence Links 1

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.1003G>T (p.Gly335Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_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). PS3_moderate - Level 2 FS: Hu et al. 2021 (PMID: 34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake. ---- part of the LDLR cycle (uptake) is less than 70% activity of wild-type, so PS3_Moderate is met. PP3 - REVEL = 0.889. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case from Hu et al. 2021 (PMID: 34970301) with 5.5mmol/L LDL under no medication, and family history of hypercholesterolemia, so Simon-Broome possible is met; so PP4 is met.
Met criteria codes
PM2
This variant is absent from gnomAD (gnomAD v2.1.1).
PS3_Moderate
Level 2 FS: Hu et al. 2021 (PMID: 34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake. ---- part of the LDLR cycle (uptake) is less than 70% activity of wild-type, so PS3_Moderate is met
Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake. PubMed:34970301
PP4
variant meets PM2 and was identified in - 2 unrelated index cases from Leren et al. 2021 (PMID: 33740630), but inclusion criteria was "No stringent criteria have been used to select hypercholesterolemic subjects for genetic testing, except that a value for total serum cholesterol of at least 6 mmol/l has been required for molecular genetic testing in adults.", which is not enough to insure clinical FH criteria, so not considered; - 1 index case from Hu et al. 2021 (PMID: 34970301) with 5.5mmol/L LDL under no medication, and family history of hypercholesterolemia, so Simon-Broome possible is met; so PP4 is met
PP3
REVEL = 0.889. It is above 0.75, so PP3 is met
Not Met criteria codes
PM3
variant identified in 1 index case from Hu et al. 2021 (PMID: 34970301) who is also heterozygous (confirmed in trans) for LDLR c.226G>C, p.Gly76Arg and has LDL of 5.62mmol/L under atorvastatin 20mg. Calculated untreated LDL: 5.62 / 0.57 (Ruel et al., 2018) = 9.86mmol/L, which is not clearly a homozygous phenotype (>13mmol/L) nor a clearly heterozygous phenotype (<8mmol/L), so not met.
PM1
variant is missense and meets PM2, but it is not in exon 4 and does not alter Cys, so not met
PM4
variant is missense, so not met
PM5
There are 4 other missense variants in the same codon: - NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) ClinVar ID 183105 - classified as Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.1003G>C (p.Gly335Arg) ClinVar ID 926520 - classified as VUS by these guidelines - NM_000527.5(LDLR):c.1004G>A (p.Gly335Asp) ClinVar ID 225181 - classified as VUS by these guidelines - NM_000527.5(LDLR):c.1004G>T (p.Gly335Val) ClinVar ID 251587 - classified as VUS by these guidelines no variant classified as Pathogenic, so not met
PM6
there is no data on de novo occurrence
BS2
Variant has not been identified in normolipidemic individuals, so not met
BS4
variant identified in - 2 relatives from Leren et al. 2021 (PMID: 33740630), but there is no data on phenotype, so not considered; - 1 family from Hu et al. 2021 (PMID: 34970301), but there are 2 variants in the family, so not considered.
BS3
Level 2 FS: Hu et al. 2021 (PMID: 34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake. ---- part of the LDLR cicle (uptake) is less than 70% activity of wild-type, so BS3 is not met
BS1
This variant is absent from gnomAD (gnomAD v2.1.1).
BP2
variant identified in 1 index case from Hu et al. 2021 (PMID: 34970301) who is also heterozygous (confirmed in trans) for LDLR c.226G>C, p.Gly76Arg and has LDL of 5.62mmol/L under atorvastatin 20mg. Calculated untreated LDL: 5.62 / 0.57 (Ruel et al., 2018) = 9.86mmol/L, which is not clearly a homozygous phenotype (>13mmol/L) nor a clearly heterozygous phenotype (<8mmol/L), so not met.
BP3
not applicable
BP4
REVEL = 0.889. It is not below 0.50, so BP4 is not met
BP1
not applicable
BP5
not applicable
BP7
variant is missense, so not met
PVS1
variant is missense and not in initiation codon, so not met
PS2
there is no data on de novo occurrence
PS4
variant meets PM2 and was identified in - 2 unrelated index cases from Leren et al. 2021 (PMID: 33740630), but inclusion criteria was "No stringent criteria have been used to select hypercholesterolemic subjects for genetic testing, except that a value for total serum cholesterol of at least 6 mmol/l has been required for molecular genetic testing in adults.", which is not enough to insure clinical FH criteria, so not considered; - 1 index case from Hu et al. 2021 (PMID: 34970301) with 5.5mmol/L LDL under no medication, and family history of hypercholesterolemia, so Simon-Broome possible is met; ---- 1 index case, not enough, so not met
PS1
There are no other variants that lead to the same amino acid change, so not met
BA1
This variant is absent from gnomAD (gnomAD v2.1.1).
PP1
variant identified in - 2 relatives from Leren et al. 2021 (PMID: 33740630), but there is no data on phenotype, so not considered; - 1 family from Hu et al. 2021 (PMID: 34970301), but there are 2 variants in the family, so not considered.
PP2
not applicable
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