NM_000859.3(HMGCR):c.2375A>G (p.Tyr792Cys) AND Muscular dystrophy, limb-girdle, autosomal recessive 28

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 21, 2023
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003236607.1

Allele description [Variation Report for NM_000859.3(HMGCR):c.2375A>G (p.Tyr792Cys)]

NM_000859.3(HMGCR):c.2375A>G (p.Tyr792Cys)

Gene:

HMGCR:3-hydroxy-3-methylglutaryl-CoA reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q13.3

Genomic location:

Preferred name:

NM_000859.3(HMGCR):c.2375A>G (p.Tyr792Cys)

HGVS:

NC_000005.10:g.75359474A>G
NG_011449.1:g.27307A>G
NM_000859.3:c.2375A>GMANE SELECT
NM_001130996.2:c.2216A>G
NM_001364187.1:c.2375A>G
NP_000850.1:p.Tyr792Cys
NP_001124468.1:p.Tyr739Cys
NP_001351116.1:p.Tyr792Cys
NC_000005.9:g.74655299A>G
NM_000859.2:c.2375A>G

Protein change:

Y739C; TYR792CYS

Links:

OMIM: 142910.0006

Molecular consequence:

NM_000859.3:c.2375A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001130996.2:c.2216A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001364187.1:c.2375A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Muscular dystrophy, limb-girdle, autosomal recessive 28
Synonyms:: Myopathy, limb-girdle, adult-onset
Identifiers:: MONDO: MONDO:0957270; MedGen: C5830518; OMIM: 620375

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003935009	OMIM	no assertion criteria provided	Pathogenic (Jun 21, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003935009

OMIM

no assertion criteria provided

Pathogenic
(Jun 21, 2023)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy.

Morales-Rosado JA, Schwab TL, Macklin-Mantia SK, Foley AR, Pinto E Vairo F, Pehlivan D, Donkervoort S, Rosenfeld JA, Boyum GE, Hu Y, Cong ATQ, Lotze TE, Mohila CA, Saade D, Bharucha-Goebel D, Chao KR, Grunseich C, Bruels CC, Littel HR, Estrella EA, Pais L, Kang PB, et al.

Am J Hum Genet. 2023 Jun 1;110(6):989-997. doi: 10.1016/j.ajhg.2023.04.006. Epub 2023 May 10.

PubMed [citation]

PMID:: 37167966
PMCID:: PMC10257193

Details of each submission

From OMIM, SCV003935009.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 sibs (family 2) with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Morales-Rosado et al. (2023) identified compound heterozygous mutations in the HMGCR gene: a c.2375A-G transition (c.2375A-G, NM_000859.2) in exon 18, resulting in a tyr792-to-cys (Y792C) substitution at a highly conserved residue in the catalytic domain, and an A-to-G transition in intron 4 (c.365+4A-G; 142910.0007), predicted to result in a splicing defect. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the gnomAD database. In vitro studies showed that the Y792C mutation reduced enzymatic activity to about 25.42% compared to wildtype; functional studies of the splice site mutation were not performed. The patients, who were 19 and 22 years of age, had onset of symptoms in the first decade and followed a rapidly progressive disease course; 1 was wheelchair-bound.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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