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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.3G>A (p.Met1Ile)

CA404071097

440536 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 670a431d-3418-42db-9be4-6e697300ad06

HGVS expressions

NM_000527.5:c.3G>A
NM_000527.5(LDLR):c.3G>A (p.Met1Ile)
NC_000019.10:g.11089551G>A
CM000681.2:g.11089551G>A
NC_000019.9:g.11200227G>A
CM000681.1:g.11200227G>A
NC_000019.8:g.11061227G>A
NG_009060.1:g.5171G>A
ENST00000558518.6:c.3G>A
ENST00000455727.6:c.3G>A
ENST00000535915.5:c.3G>A
ENST00000545707.5:c.3G>A
ENST00000557933.5:c.3G>A
ENST00000557958.1:n.89G>A
ENST00000558013.5:c.3G>A
ENST00000558518.5:c.3G>A
ENST00000560502.5:n.89G>A
NM_000527.4:c.3G>A
NM_001195798.1:c.3G>A
NM_001195799.1:c.3G>A
NM_001195800.1:c.3G>A
NM_001195803.1:c.3G>A
NM_001195798.2:c.3G>A
NM_001195799.2:c.3G>A
NM_001195800.2:c.3G>A
NM_001195803.2:c.3G>A
NR_163945.1:n.109C>T

Likely Pathogenic

Met criteria codes 3
PM2 PVS1_Moderate PM5
Not Met criteria codes 8
PS3 PS1 PP4 BA1 BS3 BS1 PM4 BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.3G>A (p.Met1Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 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 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PM5- Three other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines. Note: One other variant resulting in the same amino acid change at this codon has been reported: 1) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -PS1 not applicable as such variants must be Pathogenic.
Met criteria codes
PM2
Variant is absent from gnomAD (v2.1.1).
PVS1_Moderate
Variant is predicted to affect the initiation codon.
PM5
Three other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1A>G (p.Met1Val) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines.
Not Met criteria codes
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
Note: One other variant resulting in the same amino acid change at this codon has been reported: 1) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -PS1 not applicable as such variants must be Pathogenic.
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-01-22
Published on: 2022-04-22
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