Submissions for variant NM_000527.5(LDLR):c.1383C>T (p.Gly461=)

gnomAD frequency: 0.00003  dbSNP: rs764929176

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237794	SCV005328518	likely benign	Hypercholesterolemia, familial, 1	2024-07-02	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1383C>T (p.Gly461=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001157 (0.01157%) in the Latino-admixed population exomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required: A) not on limits B) does not create GT. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. This variant has two supporting strength evidence codes towards Benign, enough to classify as Likely Benign, and only one moderate strength evidence code towards Pathogenic. VCEP consensus is that PM2 is not strong enough evidence to upgrade the classification of an otherwise Benign or Likely Benign variant.
LDLR-LOVD, British Heart Foundation	RCV000237794	SCV000295407	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237794	SCV000322948	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles
All of Us Research Program, National Institutes of Health	RCV000237794	SCV004820308	likely benign	Hypercholesterolemia, familial, 1	2023-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020965	SCV005036035	likely benign	Cardiovascular phenotype	2023-10-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GENinCode PLC	RCV004820010	SCV005441723	likely benign	Familial hypercholesterolemia	2024-08-09	criteria provided, single submitter	clinical testing	This is a synonymous (silent) variant that is not predicted to impact splicing and occurs at a nucleotide which is not conserved. Therefore this variant has been classified as Likely Benign (BP4, BP7).