NM_058246.4(DNAJB6):c.279C>G (p.Phe93Leu) AND Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 27, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000024240.24

Allele description [Variation Report for NM_058246.4(DNAJB6):c.279C>G (p.Phe93Leu)]

NM_058246.4(DNAJB6):c.279C>G (p.Phe93Leu)

Gene:

DNAJB6:DnaJ heat shock protein family (Hsp40) member B6 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.3

Genomic location:

Preferred name:

NM_058246.4(DNAJB6):c.279C>G (p.Phe93Leu)

Other names:

DNAJB6, PHE93LEU, 279C-G

HGVS:

NC_000007.14:g.157367416C>G
NG_032573.1:g.35401C>G
NM_001363676.1:c.279C>G
NM_005494.3:c.279C>G
NM_058246.4:c.279C>GMANE SELECT
NP_001350605.1:p.Phe93Leu
NP_005485.1:p.Phe93Leu
NP_490647.1:p.Phe93Leu
NC_000007.13:g.157160110C>G
NM_005494.2:c.279C>G
NM_058246.3:c.279C>G
O75190:p.Phe93Leu

Protein change:

F93L; PHE93LEU

Links:

UniProtKB: O75190#VAR_067834; OMIM: 611332.0003; dbSNP: rs149278319

NCBI 1000 Genomes Browser:

rs149278319

Molecular consequence:

NM_001363676.1:c.279C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005494.3:c.279C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_058246.4:c.279C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (LGMDD1)
Synonyms:: MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1D; Autosomal dominant limb-girdle muscular dystrophy type 1D; MUSCULAR DYSTROPHY, AUTOSOMAL DOMINANT, WITH RIMMED VACUOLES; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0021018; MedGen: C4721885; Orphanet: 34516; OMIM: 603511

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045531	OMIM	no assertion criteria provided	Pathogenic (Feb 26, 2012)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 20682716, 21376592, 22366786, 26205529
SCV001392776	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22334415, 26205529, 28794355, 26847086, 28492532
SCV002021725	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 10, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004045925	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Oct 11, 2022)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy.

Sandell S, Huovinen S, Sarparanta J, Luque H, Raheem O, Haapasalo H, Hackman P, Udd B.

J Neurol Neurosurg Psychiatry. 2010 Aug;81(8):834-9. doi: 10.1136/jnnp.2009.192351.

PubMed [citation]

PMID:: 20682716

Four new Finnish families with LGMD1D; refinement of the clinical phenotype and the linked 7q36 locus.

Hackman P, Sandell S, Sarparanta J, Luque H, Huovinen S, Palmio J, Paetau A, Kalimo H, Mahjneh I, Udd B.

Neuromuscul Disord. 2011 May;21(5):338-44. doi: 10.1016/j.nmd.2011.02.008. Epub 2011 Mar 3.

PubMed [citation]

PMID:: 21376592

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000045531.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

Description

In 16 affected members from 5 Finnish families with limb-girdle muscular dystrophy type 1E (LGMDD1; 603511), previously reported by Sandell et al. (2010) and Hackman et al. (2011), Sarparanta et al. (2012) identified a heterozygous 279C-G transversion in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L) substitution at a highly conserved residue in the G/F domain. The mutation was not found in 202 Finnish, 104 Italian, or 215 U.S. control individuals. The F93L substitution can also be caused by a 277T-C transition (611332.0001) and a 279C-A transversion (611332.0004).

In a 57-year-old man (patient 3s) with sporadic occurrence of LGMD1E and onset at age 45, Ruggieri et al. (2015) identified a de novo heterozygous c.279C-G transversion (c.279C-G, NC_000007.14) in the DNAJB6 gene. The mutation was found by Sanger sequencing. He had proximal and distal muscle weakness affecting only the lower limbs and remained ambulatory.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001392776.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 93 of the DNAJB6 protein (p.Phe93Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 22334415, 26205529, 26847086, 28794355). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31529). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAJB6 protein function. Experimental studies have shown that this missense change affects DNAJB6 function (PMID: 26847086).

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

From Revvity Omics, Revvity, SCV002021725.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV004045925.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

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

Last Updated: Oct 20, 2024

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