5-75351562-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP5

The NM_000859.3(HMGCR):c.1328G>A(p.Arg443Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R443W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HMGCR NM_000859.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.26

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-75351561-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2506434.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, HMGCR
• PP5: Variant 5-75351562-G-A is Pathogenic according to our data. Variant chr5-75351562-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2506430.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-75351562-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCR	NM_000859.3	c.1328G>A	p.Arg443Gln	missense_variant	11/20	ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.1328G>A	p.Arg443Gln	missense_variant	11/20	1	NM_000859.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251244 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 21, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Uncertain	0.0067	D
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.053	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.55
MutPred		0.29		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.69
MPC		1.8
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.78
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs982576013; hg19: chr5-74647387;