Submissions for variant NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn)

dbSNP: rs879254862

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238500	SCV002506365	uncertain significance	Hypercholesterolemia, familial, 1	2022-01-17	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1322T>A (p.Ile441Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.859. It is above 0.75, so PP3 is Met. PM5 - 2 other missense variants in the same codon: - NM_000527.5(LDLR):c.1322T>C (p.Ile441Thr) (ClinVar ID: 251783) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) (ClinVar ID: 251784) - VUS by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.
LDLR-LOVD, British Heart Foundation	RCV000238500	SCV000295361	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238500	SCV000606391	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research