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.977C>T (p.Ser326Phe)

CA10585236

251582 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 8b8d2602-1d5a-4183-a896-7fa1f17b6d6e
Approved on: 2022-01-28
Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.977C>T
NM_000527.5(LDLR):c.977C>T (p.Ser326Phe)
NC_000019.10:g.11110688C>T
CM000681.2:g.11110688C>T
NC_000019.9:g.11221364C>T
CM000681.1:g.11221364C>T
NC_000019.8:g.11082364C>T
NG_009060.1:g.26308C>T
ENST00000558518.6:c.977C>T
ENST00000252444.9:n.1231C>T
ENST00000455727.6:c.473C>T
ENST00000535915.5:c.854C>T
ENST00000545707.5:c.596C>T
ENST00000557933.5:c.977C>T
ENST00000558013.5:c.977C>T
ENST00000558518.5:c.977C>T
ENST00000560467.1:n.541-826C>T
NM_000527.4:c.977C>T
NM_001195798.1:c.977C>T
NM_001195799.1:c.854C>T
NM_001195800.1:c.473C>T
NM_001195803.1:c.596C>T
NM_001195798.2:c.977C>T
NM_001195799.2:c.854C>T
NM_001195800.2:c.473C>T
NM_001195803.2:c.596C>T
More

Likely Pathogenic

Met criteria codes 4
PP4 PP3 PM2 PM5
Not Met criteria codes 22
BP2 BP3 BP4 BP1 BP5 BP7 BA1 PS2 PS4 PS3 PS1 PP1 PP2 PM6 PM3 PM1 PM4 BS2 PVS1 BS4 BS3 BS1

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
The NM_000527.5(LDLR):c.977C>T (p.Ser326Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, 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), so PM2 is met. PM5 - There are 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) - 2 stars, Likely pathogenic in ClinVar; Pathogenic by these guidelines (FH VCEP training August 2020). (2) NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) - 1 star, VUS in ClinVar; VUS by these guidelines (PM2, PM5, PP3) with no case data. There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is met PP3 - REVEL = 0.937. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case who fulfills SB criteria (clinical criteria according to PMID 8891383 (Chaves et al., 1996): TC and LDL-C over the 95th percentile corrected for age and sex, with TG not exceeding 200 mg/dl; plus two of the following: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative, and hypercholesterolemic children in the family) from PMID 11668640 (García-García et al. 2001), Spain; so PP4 is met
Met criteria codes
PP4
variant meets PM2 and was identified in: - 1 index case who fulfills SB criteria (clinical criteria according to PMID 8891383 (Chaves et al., 1996): TC and LDL-C over the 95th percentile corrected for age and sex, with TG not exceeding 200 mg/dl; plus two of the following: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative, and hypercholesterolemic children in the family) from PMID 11668640 (García-García et al. 2001); Spain -- so PP4 is met
PP3
REVEL = 0.937. It is above 0.75, so PP3 is met
PM2
This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met
PM5
There are 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) - 2 stars, Likely pathogenic in ClinVar - Pathogenic by these guidelines (FH VCEP training August 2020) (2) NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) - 1 star, VUS in ClinVar - VUS by these guidelines (PM2, PM5, PP3) with no case data so PM5 is met
Not Met criteria codes
BP2
variant not identified in index cases with more than 1 variant
BP3
not applicable
BP4
REVEL = 0.937. It is not below 0.50, so BP4 is not met
BP1
not applicable
BP5
not applicable
BP7
variant is missense, so BP7 is not applicable
BA1
This variant is absent from gnomAD (gnomAD v2.1.1), so BA1 is not met
PS2
no de novo occurrence
PS4
variant meets PM2 and was identified in: - 1 index case who fulfills SB criteria (clinical criteria according to PMID 8891383 (Chaves et al., 1996): TC and LDL-C over the 95th percentile corrected for age and sex, with TG not exceeding 200 mg/dl; plus two of the following: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative, and hypercholesterolemic children in the family) from PMID 11668640 (García-García et al. 2001); Spain -- not enough, so PS4 is not met
PS3
There are no functional studies published for this variant
PS1
no other variant leads to the same amino acid change, so PS1 is not met
PP1
no segregation data
PP2
not applicable
PM6
no de novo occurrence
PM3
variant not identified in index cases with more than 1 variant
PM1
variant meets PM2 and is missense, but it is not in exon 4 and does not alter Cys, so not met
PM4
variant is missense, so PM4 is not applicable
BS2
variant not identified in normolipidemic individuals: not identified in 60 healthy controls from PMID 11668640, so not met
PVS1
variant is missense and not in initiation codon, so PVS1 is not applicable
BS4
no segregation data
BS3
There are no functional studies published for this variant
BS1
This variant is absent from gnomAD (gnomAD v2.1.1), so BS1 is not met
Curation History
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