NM_001849.4(COL6A2):c.1865G>T (p.Ser622Ile) AND Collagen 6-related myopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 5, 2024
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:: RCV003994665.1

Allele description [Variation Report for NM_001849.4(COL6A2):c.1865G>T (p.Ser622Ile)]

NM_001849.4(COL6A2):c.1865G>T (p.Ser622Ile)

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.1865G>T (p.Ser622Ile)

HGVS:

NC_000021.9:g.46125513G>T
NG_008675.1:g.32395G>T
NM_001849.4:c.1865G>TMANE SELECT
NM_058174.3:c.1865G>T
NM_058175.3:c.1865G>T
NP_001840.3:p.Ser622Ile
NP_001840.3:p.Ser622Ile
NP_478054.2:p.Ser622Ile
NP_478055.2:p.Ser622Ile
LRG_476t1:c.1865G>T
LRG_476:g.32395G>T
LRG_476p1:p.Ser622Ile
NC_000021.8:g.47545427G>T
NM_001849.3:c.1865G>T

Protein change:

S622I

Molecular consequence:

NM_001849.4:c.1865G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_058174.3:c.1865G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_058175.3:c.1865G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Collagen 6-related myopathy
Synonyms:: Collagen VI-related myopathy
Identifiers:: MONDO: MONDO:0100225; MedGen: CN117976

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Homo sapiens PAXX non-homologous end joining factor (PAXX), transcript variant 5...
Homo sapiens PAXX non-homologous end joining factor (PAXX), transcript variant 5, non-coding RNA
gi|1701973469|ref|NR_138075.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004812526	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 5, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32528171, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812526

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 5, 2024)

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

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.

Töpf A, Johnson K, Bates A, Phillips L, Chao KR, England EM, Laricchia KM, Mullen T, Valkanas E, Xu L, Bertoli M, Blain A, Casasús AB, Duff J, Mroczek M, Specht S, Lek M, Ensini M, MacArthur DG; MYO-SEQ consortium., Straub V.

Genet Med. 2020 Sep;22(9):1478-1488. doi: 10.1038/s41436-020-0840-3. Epub 2020 Jun 11.

PubMed [citation]

PMID:: 32528171
PMCID:: PMC7462745

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812526.1

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

Description

This sequence change in COL6A2 is predicted to replace serine with isoleucine at codon 622, p.(Ser622Ile). The serine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the second von Willebrand factor type A domain. There is a large physicochemical difference between serine and isoleucine. This variant is absent from the population database gnomAD v4.0. To our knowledge, this variant is novel and has not been previously reported in the relevant scientific literature or databases. Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.9). Another missense variant c.1865G>A p.(Ser622Asn) in the same codon has been reported in individuals with phenotypes consistent with collagen 6-related myopathy (PMID: 32528171; ClinVar: SCV001390923.4). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.

#	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 20, 2024

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