5-75359992-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000859.3(HMGCR):c.2465G>A(p.Gly822Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGCR NM_000859.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

Genes affected

HMGCR (HGNC:5006): (3-hydroxy-3-methylglutaryl-CoA reductase) HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

CERT1 (HGNC:2205): (ceramide transporter 1) This gene encodes a kinase that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture disease is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HMGCR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 5-75359992-G-A is Pathogenic according to our data. Variant chr5-75359992-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1803007.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCR	NM_000859.3	c.2465G>A	p.Gly822Asp	missense_variant	19/20	ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.2465G>A	p.Gly822Asp	missense_variant	19/20	1	NM_000859.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Muscular dystrophy, limb-girdle, autosomal recessive 28 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 21, 2023

- -

Limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

The Morris Kahn Laboratory of Human Genetics, Ben-Gurion University of the Negev

Dec 03, 2022

Genome-wide linkage analysis, through SNP genotyping for 6 affected individuals and 10 unaffected family members, identified a single 3.2Mbp homozygous segment on chromosome 5q13.2-q13.3, that was shared among all affected individuals and was either absent or in a heterozygous state in unaffected individuals. The disease-associated locus, spanning between SNPs rs2129403 and rs2914143, 5:73803333-77084175 (GRCh38/hg38), showed a maximal LOD score of 4.8204 at rs4345300. Filtering through whole-exome sequencing data of 2 patients, only a single variant was found within the 3.2 Mbp locus: g.5:75359992G>A (GRCh38/hg38); NM_000859.3 :c.2465G>A; p.(G822D) in HMGCR. The variant is a singleton, is not present in large genomic databases, predicted to be pathogenic according to SIFT and PolyPhen2 algorithms and has a CADD score of 29.6. The homozygous mutated nucleotide, coded amino acid, and the entire gene sequence are highly conserved throughout evolution. The Glycine to Aspartate substitution at position 822 is a radical replacement, predicted to interfere with several peptide bonds, disrupt helix-dipole and cause charge-based repulsion, with possible detrimental impact on secondary and tertiary structure of HMG-CoA reductase. Within the locus, there were no other variants, nor were there any variants in genes known to cause LGMD and LGMD-like diseases throughout the exomes. The HMGCR variant was validated via restriction analysis and Sanger sequencing and was found to fully segregate as expected for autosomal recessive heredity. Of 190 non-related ethnically matched controls of Bedouin tribes other than the one affected, none carried the variant. Screening of 20 individuals of the same tribe did not show other carriers. Functional characterization by spectro-colorimetric analysis of the WT and mutant proteins’ function using an NADPH-oxidation assay demonstrated that, compared to its WT counterpart, the mutant protein had 69% reduction in Vmax and 65% increase in Km in relation to the substrate HMG-CoA, indicating lower affinity of the mutated protein for HMG-CoA, as well as overall slower reaction-rate. This was also supported by ITC analysis of HMG-CoA reductase thermodynamics to a known inhibitor, pravastatin. While the WT protein exhibited a mild exothermic reaction, the mutant form displayed kinetics almost identical to a no-protein control, indicating that the catalytic pocket of the mutant protein has a very low affinity towards pravastatin. To conclude, the HMGCR variant was found to be pathogenic according to ACMG criteria PM2, PP3,PS3, PP4 and PP1 (moderate to strong). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;.;.
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.5	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.025	D;D;D;T
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.93	P;P;D;.
Vest4		0.93
MutPred		0.94		Loss of catalytic residue at V823 (P = 0.119);Loss of catalytic residue at V823 (P = 0.119);.;.;
MVP		0.71
MPC		2.1
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.84
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-74655817;