NM_001848.3(COL6A1):c.428+1G>A AND Bethlem myopathy 1A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 30, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000018716.33

Allele description [Variation Report for NM_001848.3(COL6A1):c.428+1G>A]

NM_001848.3(COL6A1):c.428+1G>A

Gene:

COL6A1:collagen type VI alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_001848.3(COL6A1):c.428+1G>A

HGVS:

NC_000021.9:g.45984470G>A
NG_008674.1:g.7722G>A
NM_001848.3:c.428+1G>AMANE SELECT
LRG_475t1:c.428+1G>A
LRG_475:g.7722G>A
NC_000021.8:g.47404384G>A
NM_001848.2:c.428+1G>A

Note:

ClinGen staff contributed the HGVS expression for this variant.

Nucleotide change:

IVS3DS, G-A, +1

Links:

OMIM: 120220.0008; dbSNP: rs1569517717

NCBI 1000 Genomes Browser:

rs1569517717

Molecular consequence:

NM_001848.3:c.428+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Bethlem myopathy 1A
Synonyms:: Myopathy, benign congenital, with contractures; Bethlem myopathy 1
Identifiers:: MONDO: MONDO:0024530; MedGen: CN029274; Orphanet: 610; OMIM: 158810

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000038999	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2002)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 7881296, 11932968
SCV002240261	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 30, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11932968, 28831785, 25535305, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000038999

OMIM

no assertion criteria provided

Pathogenic
(Apr 1, 2002)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV002240261

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 30, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Bethlem myopathy: early-onset benign autosomal dominant myopathy with contractures. Description of two new families.

Merlini L, Morandi L, Granata C, Ballestrazzi A.

Neuromuscul Disord. 1994 Sep-Nov;4(5-6):503-11.

PubMed [citation]

PMID:: 7881296

Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy.

Vanegas OC, Zhang RZ, Sabatelli P, Lattanzi G, Bencivenga P, Giusti B, Columbaro M, Chu ML, Merlini L, Pepe G.

Muscle Nerve. 2002 Apr;25(4):513-9.

PubMed [citation]

PMID:: 11932968

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000038999.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In affected members of an Italian family with Bethlem myopathy (BTHLM1A; 158810) previously reported by Merlini et al. (1994), Vanegas et al. (2002) identified a heterozygous G-to-A transition at the +1 position of intron 3 of the COL6A1 gene. The mutation results in the activation of a cryptic splice donor site at the 3-prime end of exon 3, leading to an in-frame deletion of 22 amino acids from codon 122 to 143 within the NH2-globular domain. Fibroblast studies showed that the mutated mRNA was stable, but the mutated protein could not be detected, suggesting that it was highly unstable and rapidly degraded.

#	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 Invitae, SCV002240261.3

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

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with the activation of a cryptic splice site in exon 3 (PMID: 11932968). Disruption of this splice site has been observed in individual(s) with Bethlem myopathy (PMID: 11932968, 28831785, 25535305). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17176). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 3 of the COL6A1 gene. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 22 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.

#	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

Last Updated: Apr 15, 2024

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