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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003935009OMIM
no assertion criteria provided
Pathogenic
(Jun 21, 2023) 		germlineliterature only

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024