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Variant: NM_000527.5(LDLR):c.1907G>T (p.Gly636Val)

CA404092833

438327 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: eb261d6d-5b82-4062-81ae-fb8ba048cd2c

HGVS expressions

NM_000527.5:c.1907G>T
NM_000527.5(LDLR):c.1907G>T (p.Gly636Val)
NC_000019.10:g.11120153G>T
CM000681.2:g.11120153G>T
NC_000019.9:g.11230829G>T
CM000681.1:g.11230829G>T
NC_000019.8:g.11091829G>T
NG_009060.1:g.35773G>T
ENST00000558518.6:c.1907G>T
ENST00000252444.9:n.2161G>T
ENST00000455727.6:c.1403G>T
ENST00000535915.5:c.1784G>T
ENST00000545707.5:c.1526G>T
ENST00000557933.5:c.1907G>T
ENST00000558013.5:c.1907G>T
ENST00000558518.5:c.1907G>T
ENST00000559340.1:n.488G>T
NM_000527.4:c.1907G>T
NM_001195798.1:c.1907G>T
NM_001195799.1:c.1784G>T
NM_001195800.1:c.1403G>T
NM_001195803.1:c.1526G>T
NM_001195798.2:c.1907G>T
NM_001195799.2:c.1784G>T
NM_001195800.2:c.1403G>T
NM_001195803.2:c.1526G>T

Uncertain Significance

Met criteria codes 3
PP3 PP4 PM2
Not Met criteria codes 19
BA1 PVS1 BS2 BS4 BS3 BS1 BP4 BP2 BP7 PS1 PS2 PS3 PS4 PP1 PM1 PM3 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 1.1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1907G>T (p.Gly636Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.977. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 1 index case who fulfills SB criteria for FH [(1) for adults, TC>7.8 mmol/L or LDL>.4.4 mmol/L; (2) for children <16 years old, TC>6.7 mmol/L; (3) patients or their relatives have tendon xanthomas; (4) patients with xanthomas whose TC > 16 mmol/L are diagnosed as homozygous and the others patients are diagnosed as heterozygous] from China (PMID: 24671153), so PP4 is Met.
Met criteria codes
PP3
REVEL = 0.977. It is above 0.75, so PP3 is Met.
PP4
Variant meets PM2 and is identified in 1 index case who fulfills SB criteria for FH[(1) for adults, TC>7.8 mmol/L or LDL>.4.4 mmol/L; (2) for children <16 years old, TC>6.7 mmol/L; (3) patients or their relatives have tendon xanthomas; (4) patients with xanthomas whose TC > 16 mmol/L are diagnosed as homozygous and the others patients are diagnosed as heterozygous] from China (PMID: 24671153), so PP4 is Met.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.
Not Met criteria codes
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.
PVS1
Variant is missense, so PVS1 is Not Met.
BS2
No control individuals tested, so BS2 is Not Met.
BS4
Variant does not segregate with FH phenotype in 2 informative meiosis from 1 family (minimum 2) from China (PMID: 24671153): 1 affected family member (LDL=5.71 mmol/L) do not has the variant and 1 non-affected family member (TC=4.93 mmol/L and LDL=3.10 mmol/L) has the variant. Lack of segregation should occur in >= 2 families, so BS4 is Not Met.
BS3
Level 1 assays: PMID 24671153: Heterologous cells (HEK-293), FACS and CLSM assays - result - 70% cell surface LDLR and internalization. ---- Assay result is not >90% in expression and functional study is not consistent with no damaging effect, so BS3 is Not Met.
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.
BP4
REVEL = 0.977. It is not below 0.50, so BP4 is Not Met.
BP2
Not observed in trans with other LP/P variants, so BP2 is Not Met.
BP7
Variant is not synonymous, so BP7 is Not Met.
PS1
No more missense variants that lead to the same amino acid change, so PS1 is Not Met.
PS2
de novo occurrence data not reported, so PS2 is Not Met.
PS3
Level 1 assays: PMID 24671153: Heterologous cells (HEK-293), FACS and CLSM assays - result - 70% cell surface LDLR and internalization. ---- functional study is not consistent with damaging effect (results are not below 70%), so PS3 is Not Met.
PS4
Variant meets PM2 and is identified in only 1 index case who fulfills SB criteria for FH[(1) for adults, TC>7.8 mmol/L or LDL>.4.4 mmol/L; (2) for children <16 years old, TC>6.7 mmol/L; (3) patients or their relatives have tendon xanthomas; (4) patients with xanthomas whose TC > 16 mmol/L are diagnosed as homozygous and the others patients are diagnosed as heterozygous] from China (PMID: 24671153), so PS4 is not met.
PP1
Variant segregates with FH phenotype in 1 informative meiosis (minimum 2) from 1 family from China (PMID: 24671153): 1 affected family member (LDL=5.7 mmol/L) has the variant, so PP1 is not met.
PM1
Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.
PM3
Not observed in trans with other LP/P variants, so PM3 is Not Met.
PM4
Variant meets PM2 but is missense, so PM4 is Not Met.
PM5
2 other missense variant(s) in the same codon: - NM_000527.5(LDLR):c.1906G>A (p.Gly636Ser) (ClinVar ID: 252109) - VUS by these guidelines - NM_000527.5(LDLR):c.1907G>A (p.Gly636Asp) (ClinVar ID: 252110) - VUS by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.
PM6
de novo occurrence data not reported, so PM6 is Not Met.
Approved on: 2022-08-29
Published on: 2022-12-23
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