Evidence Repository - Clinical Genome Resources

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.284G>A (p.Cys95Tyr)

CA10584826

251113 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: de75f52a-4aaa-4b08-a993-f560e5b916a0

Approved on: 2024-02-23

Published on: 2025-08-29

HGVS expressions

NM_000527.5(LDLR):c.284G>A (p.Cys95Tyr)

NM_000527.5:c.284G>A

NC_000019.10:g.11102757G>A

CM000681.2:g.11102757G>A

NC_000019.9:g.11213433G>A

CM000681.1:g.11213433G>A

NC_000019.8:g.11074433G>A

NG_009060.1:g.18377G>A

ENST00000252444.10:c.542G>A

ENST00000559340.2:c.284G>A

ENST00000560467.2:c.284G>A

ENST00000558518.6:c.284G>A

ENST00000252444.9:c.538G>A

ENST00000455727.6:c.284G>A

ENST00000535915.5:c.190+2412G>A

ENST00000545707.5:c.284G>A

ENST00000557933.5:c.284G>A

ENST00000557958.1:n.370G>A

ENST00000558013.5:c.284G>A

ENST00000558518.5:c.284G>A

NM_000527.4:c.284G>A

NM_001195798.1:c.284G>A

NM_001195799.1:c.190+2412G>A

NM_001195800.1:c.284G>A

NM_001195803.1:c.284G>A

NM_001195798.2:c.284G>A

NM_001195799.2:c.190+2412G>A

NM_001195800.2:c.284G>A

NM_001195803.2:c.284G>A

Likely Pathogenic

PP4 PP3 PM2 PM1

BS2 BS4 BS3 BS1 BP3 BP4 BP1 PVS1 BP5 BP7 BA1 PS4 PS3 PP1 PP2 PM5 PM4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.284G>A (p.Cys95Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.918. PM1: Variant meets PM2 and alters one higly conserved Cys residue (Cys95). PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling Simon Broome criteria or with DLCN score >=6, after alternative causes of high cholesterol were excluded, from PMID 28502510 (Bañares et al., 2017).

PP4

- PP4: Variant meets PM2 and is identified in at least 1 index case fulfilling DLCN>=6 criteria or SB criteria for FH, after alternative causes of high cholesterol are excluded from PMID:28502510. (in this PMID, childreen fulfilled SB criteria for FH and adults fulfilled DLCN>=6 criteria. It is not stated if the index case with the variant is an adult or a child, however, for both cohorts FH specific criteria is fulfilled).

PP3

- PP3: REVEL = 0.918. It is above 0.75, so PP3 is met.

PM2

- PM2: This variant is absent from gnomAD (gnomAD v2.1.1).

PM1

- PM1: Variant meets PM2 and alters one higly conserved Cys residue (Cys95).

BS2

* BS2 / BS4 / PP1: not met, (no information of several index cases or segregation data/cases in different families)

BS4

* BS2 / BS4 / PP1: not met, (no information of several index cases or segregation data/cases in different families)

BS3

* BS3 / PS3: not met (no information or reports of functional data).

BS1

This variant is absent from gnomAD (gnomAD v2.1.1), therefore BS1 is not met.

BP3

N/A according to FH VCEP Guidelines

BP4

BP4: REVEL = 0.918, not bellow 0.50. Therefore, BP4 is not met.

BP1

N/A according to FH VCEP Guidelines

PVS1

This variant is misense, therefore PVS1 is not met.

BP5

N/A according to FH VCEP Guidelines

BP7

This variant is misense, therefore BP7 is not met.

BA1

This variant is absent from gnomAD (gnomAD v2.1.1), therefore BA1 is not met.

PS4

* PS4: (PMID:18096825) Variant meets PM2 and is identified in 3 index cases from the Spanish FH register. Specific clinical data is presented in Table 1, only with mean range values of age/CT/LDL. Since clinical and familial data of these 3 subjects is unclear, they were not counted towards PS4 "All patients had been referred to the Lipid Clinic of Hospital Clínic in Barcelona for diagnosis of severe hypercholesterolemia or alleged refractoriness to treatment (...) Subjects underwent sonographic assessment of femoral atherosclerosis (...) Subjects with clinical FH are recruited into the Spanish FH Register (...) All subjects were assessed for family history of early-onset CHD, clinical history, medication use, CV risk and presence of tendon xanthomas". // (PMID:19318025) at least 1 index case with the variant and DLCN criteria≥ 6, supp material was not possible to access to confirm the variant and number of cases // (PMID:23375686) Variant identified in at least one index case fulfilling DLCN criteria for "possible", "probable" or "definite FH", after alternative causes of high cholesterol are excluded. As it is not stated DLCN score of this index case, this case was not counted.

PS3

* BS3 / PS3: not met (no information or reports of functional data).

PP1

* BS2 / BS4 / PP1: not met, (no information of several index cases or segregation data/cases in different families)

PP2

N/A according to FH VCEP Guidelines

PM5

* PM5 / PS1 not met: NM_000527.5(LDLR):c.283T>G (p.Cys95Gly) (ClinVar ID: 251112) considered as VUS by these guidelines

PM4

This variant is misense, therefore PM4 is not met.

Curation History

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