NM_001849.4(COL6A2):c.1312G>A (p.Asp438Asn) AND Bethlem myopathy 1A

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 4, 2023
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:: RCV001859591.6

Allele description [Variation Report for NM_001849.4(COL6A2):c.1312G>A (p.Asp438Asn)]

NM_001849.4(COL6A2):c.1312G>A (p.Asp438Asn)

Gene:

COL6A2:collagen type VI alpha 2 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_001849.4(COL6A2):c.1312G>A (p.Asp438Asn)

HGVS:

NC_000021.9:g.46119830G>A
NG_008675.1:g.26712G>A
NM_001849.4:c.1312G>AMANE SELECT
NM_058174.3:c.1312G>A
NM_058175.3:c.1312G>A
NP_001840.3:p.Asp438Asn
NP_001840.3:p.Asp438Asn
NP_478054.2:p.Asp438Asn
NP_478055.2:p.Asp438Asn
LRG_476t1:c.1312G>A
LRG_476:g.26712G>A
LRG_476p1:p.Asp438Asn
NC_000021.8:g.47539744G>A
NM_001849.3:c.1312G>A

Protein change:

D438N

Links:

dbSNP: rs202039679

NCBI 1000 Genomes Browser:

rs202039679

Molecular consequence:

NM_001849.4:c.1312G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_058174.3:c.1312G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_058175.3:c.1312G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002299330	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31069529, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002299330

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 4, 2023)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients.

Ganapathy A, Mishra A, Soni MR, Kumar P, Sadagopan M, Kanthi AV, Patric IRP, George S, Sridharan A, Thyagarajan TC, Aswathy SL, Vidya HK, Chinnappa SM, Nayanala S, Prakash MB, Raghavendrachar VG, Parulekar M, Gowda VK, Nampoothiri S, Menon RN, Pachat D, Udani V, et al.

J Neurol. 2019 Aug;266(8):1919-1926. doi: 10.1007/s00415-019-09358-1. Epub 2019 May 8.

PubMed [citation]

PMID:: 31069529

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002299330.3

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

Description

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 not expected to disrupt COL6A2 protein function. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 438 of the COL6A2 protein (p.Asp438Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of COL6A2-related conditions (PMID: 31069529). ClinVar contains an entry for this variant (Variation ID: 284090). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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