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]

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Variant: NM_000527.5(LDLR):c.1A>T (p.Met1Leu)

CA10584720

250968 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: be29245c-5ccb-4a73-8acb-9d5bb0810775

HGVS expressions

NM_000527.5:c.1A>T

NM_000527.5(LDLR):c.1A>T (p.Met1Leu)

NC_000019.10:g.11089549A>T

CM000681.2:g.11089549A>T

NC_000019.9:g.11200225A>T

CM000681.1:g.11200225A>T

NC_000019.8:g.11061225A>T

NG_009060.1:g.5169A>T

ENST00000558518.6:c.1A>T

ENST00000455727.6:c.1A>T

ENST00000535915.5:c.1A>T

ENST00000545707.5:c.1A>T

ENST00000557933.5:c.1A>T

ENST00000557958.1:n.87A>T

ENST00000558013.5:c.1A>T

ENST00000558518.5:c.1A>T

ENST00000560502.5:n.87A>T

NM_000527.4:c.1A>T

NM_001195798.1:c.1A>T

NM_001195799.1:c.1A>T

NM_001195800.1:c.1A>T

NM_001195803.1:c.1A>T

NM_001195798.2:c.1A>T

NM_001195799.2:c.1A>T

NM_001195800.2:c.1A>T

NM_001195803.2:c.1A>T

NR_163945.1:n.111T>A

Pathogenic

PS1 PS3 PP4 PVS1_Moderate PM2 PS4_Supporting

PS2 BP4 BP1 BP2 BP3 BP7 BP5 BA1 PP3 PP2 PP1 PM3 PM4 PM1 PM5 PM6 BS2 BS4 BS3 BS1

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1A>T (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS1, PS3, PM2, PVS1_Moderate, PP4 and PS4_Supporting 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: PS1 - One more missense variant that leads to the same amino acid change: (1)NM_000527.5(LDLR):c.1A>C (p.Met1Leu) (ClinVar ID 250966) - Pathogenic by these guidelines --- variant is classified as Pathogenic, so PS1 is Met. PS3 - Level 1 (and other levels) FS: Graça et al., 2021 (PMID 34572405) Heterologous cells (CHO), FACS, luciferase and microscopy assays: FACS: 10% cell surface LDLR, 3% binding and 8% uptake; luciferase : 1% luciferase construct activity; microscopy: 5-10% LDLR expression and 5-10% LDLR activity. --- functional study in heterologous cells results in expression, binding and uptake less than 70% of wild-type, so PS3 is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PVS1_moderate - Variant is in initiation codon, so PVS1_Moderate is Met. PS4_supporting - Variant meets PM2 and was identified in: - 1 index case with DLCN score above 6 from University of British Columbia, Canada; - 1 index case with Simon-Broome criteria of possible FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 1 index case with Simon-Broome criteria of possible FH (Inclusion: LDL-C level>95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, and a family history of hypercholesterolemia and cardiovascular disease) from PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; - 1 index case with Simon-Broome criteria of at least possible FH from PMID: 17094996 (Tosi et al., 2007), UK. --- 4 cases, so PS4_Supporting is Met PP4 - Variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical FH criteria from different labs (see PS4 for details), so PP4 is Met.

PS1

One more missense variant that leads to the same amino acid change: (1)NM_000527.5(LDLR):c.1A>C (p.Met1Leu) (ClinVar ID 250966) - Pathogenic by these guidelines --- variant is classified as Pathogenic, so PS1 is Met

PS3

Level 1 (and other levels) FS: Graça et al., 2021 (PMID 34572405) Heterologous cells (CHO), FACS, luciferase and microscopy assays: FACS: 10% cell surface LDLR, 3% binding and 8% uptake; luciferase : 1% luciferase construct activity; microscopy: 5-10% LDLR expression and 5-10% LDLR activity. --- functional study in heterologous cells results in expression, binding and uptake less than 70% of wild-type, so PS3 is met.

PP4

Variant meets PM2 and was identified in: - 1 index case with DLCN score above 6 from University of British Columbia, Canada; - 1 index case with Simon-Broome criteria of possible FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 1 index case with Simon-Broome criteria of possible FH (Inclusion: LDL-C level>95th percentile for age and gender and autosomal dominant inheritance pattern of hypercholesterolemia, and a family history of hypercholesterolemia and cardiovascular disease) from PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; - 1 index case with Simon-Broome criteria of at least possible FH from PMID: 17094996 (Tosi et al., 2007), UK. --- so PP4 is Met

PVS1_Moderate

Variant is in initiation codon, so PVS1_Moderate is Met

PM2

This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.

PS4_Supporting

PS2

no de novo cases were identified, so PS2 is Not Met

BP4

PVS1_Moderate is Met, so BP4 is not applicable.

BP1

Not applicable

BP2

not identified in individuals with other variants, so BP2 is Not Met

BP3

Not applicable

BP7

Missense variant, so BP7 is not applicable

BP5

Not applicable

BA1

This variant was not identified in gnomAD (gnomAD v2.1.1), so BA1 is not met.

PP3

PVS1_Moderate is Met, so PP3 is not applicable.

PP2

Not applicable

PP1

Variant segregates with FH phenotype in - 1 informative meiosis from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 1 relative has the variant and the phenotype. --- not enough for PP1, so not met

PM3

not identified in individuals with other variants, so PM3 is Not Met

PM4

Variant is missense, so not applicable

PM1

Variant is missense and PM2 is Met, but it is not in exon 4 nor changes any of the 60 Cys residues listed, so PM1 is Not Met

PM5

Four more missense variants described in same codon, that lead to different amino acid changes: (1)NM_000527.5(LDLR):c.1A>G (p.Met1Val) (ClinVar ID 250967) - Likely pathogenic by these guidelines (2)NM_000527.4(LDLR):c.2T>C (p.Met1Thr) (ClinVar ID 441174) - Likely pathogenic by these guidelines (3)NM_000527.4(LDLR):c.3G>A (p.Met1Ile) (ClinVar ID 440536) - Likely pathogenic by these guidelines (4)NM_000527.5(LDLR):c.3G>T (p.Met1Ile) (ClinVar ID 250969) - Likely pathogenic by these guidelines --- no other variant is classified as Pathogenic by these guidelines, so PM5 is Not Met.

PM6

no de novo cases were identified, so PM6 is Not Met

BS2

no unaffected individuals identified with the variant, so BS2 is Not Met

BS4

no lack of segregation was observed, so BS4 is Not Met

BS3

BS1

This variant was not identified in gnomAD (gnomAD v2.1.1), so BS1 is not met.

Approved on: 2022-03-17

Published on: 2022-07-12

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