NM_000859.3:c.1327C>T

Variant names:

• chr5-75351561-C-T
• rs951205085
• NM_000859.3:c.1327C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_000859.3(HMGCR):​c.1327C>T​(p.Arg443Trp) variant causes a missense change involving the alteration of a non-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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R443Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGCR NM_000859.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.55

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 chr5-75351562-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• PP5: Variant 5-75351561-C-T is Pathogenic according to our data. 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. Variant chr5-75351561-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.1327C>T	p.Arg443Trp	missense_variant	Exon 11 of 20	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.1327C>T	p.Arg443Trp	missense_variant	Exon 11 of 20	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Jun 21, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.8	M;M;M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.58
MutPred		0.41		Loss of disorder (P = 0.0034);Loss of disorder (P = 0.0034);Loss of disorder (P = 0.0034);
MVP		0.61
MPC		2.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs951205085; hg19: chr5-74647386;