Submissions for variant NM_000527.5(LDLR):c.3G>T (p.Met1Ile)

dbSNP: rs879254383

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237500	SCV002506388	likely pathogenic	Hypercholesterolemia, familial, 1	2022-01-22	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.3G>T (p.Met1Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, PM5, PP1, 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 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PP1- variant segregates with phenotype in 2 informative meioses in 1 family (Centre for Cardiovascular Surgery and Transplantation - 1 family: 2 affected relatives with the variant). PP4 - variant meets PM2 and is identified in 1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. 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_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. -PS1 is not applicable as such variants must be Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000237500	SCV000294408	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	research
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237500	SCV000540712	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt initiation codon.