Submissions for variant NM_000527.5(LDLR):c.409G>A (p.Gly137Ser)

gnomAD frequency: 0.00002  dbSNP: rs730882082

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237389	SCV000294690	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237389	SCV000540731	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000161956	SCV001246002	likely pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193789	SCV001362900	pathogenic	Familial hypercholesterolemia	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.409G>A (p.Gly137Ser) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251184 control chromosomes. c.409G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Cameron_2012, Damgaard_2005, Dube_2015, Leren_2021). These data indicate that the variant is very likely to be associated with disease. One study (Dube_2015) determined the frequency of the variant in Inuit general population from Alaska, Canada and Greenland to be relatively high at 10%. Authors stratified plasma lipoprotein profiles according to LDLR p.Gly137Ser genotype and determined that carriers had approximately a 3-fold increased risk of hypercholesterolemia, but did not have classical familial hypercholesterolemia. They finally concluded that the variant is a common, dysfunctional variant in Inuit that is strongly associated with a large LDL cholesterol-raising effect, although not causing classical FH. Another study has further corroborated these findings reporting this variant as conferring a high risk for familial hypercholesterolemia in 30% of Greenlanders (example, Jorsboe_2022). At least two publications report conflicting experimental evidence evaluating an impact on protein function. One study demonstrated the variant to confer no effect on LDL uptake (Thormaehlen_2015) while another study determined it caused a significant 61% reduction in LDL binding ability (Dube_2015). The following publications have been ascertained in the context of this evaluation (PMID: 22683370, 15823288, 25414273, 36267056, 33740630, 25647241). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (LP, n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000161956	SCV001817776	uncertain significance	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Identified in a patient with familial hypercholesterolemia and in a second patient with myocardial infarction, however, additional clinical and segregation information was not included (PMID: 15823288, 25414273); Functional studies have inconsistent results; while one study shows this variant leads to reduced binding activity, another analysis indicates that G137S has no effect on LDL uptake compared to wild type (PMID: 25647241, 25414273); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25487149, 29431662, 28286704, 26321433, 22683370, 30583242, 37937776, 36580209, 25647241, 15823288, 36969703, 36190978, 36267056, 34407635, 33740630, 25414273, 34906454)
Ambry Genetics	RCV003372631	SCV004085589	likely pathogenic	Cardiovascular phenotype	2023-08-15	criteria provided, single submitter	clinical testing	The p.G137S variant (also known as c.409G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 409. The glycine at codon 137 is replaced by serine, an amino acid with similar properties. This alteration, which is also known as p.G116S, has been reported in familial hypercholesterolemia (FH) cohorts, including a case control study of the Inuit population (Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Cameron J et al. Transl Res, 2012 Aug;160:125-30; Dubé JB et al. Circ Cardiovasc Genet, 2015 Feb;8:100-5; Björnsson E et al. Arterioscler Thromb Vasc Biol, 2021 Oct;41:2616-2628; Leren TP et al. Atherosclerosis, 2021 Apr;322:61-66; Jørsboe E et al. HGG Adv, 2022 Oct;3:100118). An in vitro study showed this alteration had reduction in ligand binding compared to wild-type (Dubé JB et al. Circ Cardiovasc Genet, 2015 Feb;8:100-5). Internal structural analysis demonstrated this alteration is moderately destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001193789	SCV005837068	likely pathogenic	Familial hypercholesterolemia	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 137 of the LDLR protein (p.Gly137Ser). This variant is present in population databases (rs730882082, gnomAD 0.003%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15823288, 25414273, 25487149, 33740630, 36267056). It is commonly reported in individuals of Arctic Inuit/Greenlander ancestry (PMID: 25414273, 36267056). This variant is also known as G116S. ClinVar contains an entry for this variant (Variation ID: 183087). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25414273). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161956	SCV000189531	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237389	SCV000606108	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004745229	SCV005344426	likely pathogenic	LDLR-related disorder	2024-06-13	no assertion criteria provided	clinical testing	The LDLR c.409G>A variant is predicted to result in the amino acid substitution p.Gly137Ser. This variant has been reported in patients with hypercholesterolemia (reported as G116S in Damgaard et al. 2005. PubMed ID: 15823288; Dubé et al. 2015. PubMed ID: 25414273; Jensson et al. 2023. PubMed ID: 37937776). One functional study showed this variant caused 60% reduced ligand binding activity compared to wild-type (Dubé et al. 2015. PubMed ID: 25414273) whereas another study showed no effect on LDL uptake (Thormaehlen et al. 2015. PubMed ID: 25647241). Of note, other missense variants affecting the same amino acid (p.Gly137Val, p.Gly137Cys) have also been reported to be pathogenic for hypercholesterolemia (HGMD). This variant is interpreted as likely pathogenic.