NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jan 8, 2025
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:: RCV000177877.45

Allele description [Variation Report for NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)]

NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)

Gene:

COL6A3:collagen type VI alpha 3 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q37.3

Genomic location:

Preferred name:

NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)

Other names:

COL6A3, LYS2483GLU (rs139260335)

HGVS:

NC_000002.12:g.237344571T>C
NG_008676.1:g.74637A>G
NM_004369.4:c.7447A>GMANE SELECT
NM_057166.5:c.5626A>G
NM_057167.4:c.6829A>G
NP_004360.2:p.Lys2483Glu
NP_004360.2:p.Lys2483Glu
NP_476507.3:p.Lys1876Glu
NP_476508.2:p.Lys2277Glu
LRG_473t1:c.7447A>G
LRG_473:g.74637A>G
LRG_473p1:p.Lys2483Glu
NC_000002.11:g.238253214T>C
NM_004369.3:c.7447A>G

Protein change:

K1876E; LYS2483GLU

Links:

OMIM: 120250.0012; dbSNP: rs139260335

NCBI 1000 Genomes Browser:

rs139260335

Molecular consequence:

NM_004369.4:c.7447A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_057166.5:c.5626A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_057167.4:c.6829A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000331642	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Apr 5, 2017)	germline	clinical testing	Citation Link,
SCV000564904	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jan 8, 2025)	germline	clinical testing	Citation Link,
SCV001449836	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001962365	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Sep 1, 2021)	germline	clinical testing	Citation Link,
SCV003829720	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005197627	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	11	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Eurofins Ntd Llc (ga), SCV000331642.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	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	unknown	not provided	not provided	not provided		11	not provided	not provided	not provided

From GeneDx, SCV000564904.12

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

Description

Reported previously in the compound heterozygous state and in the homozygous state in patients with Bethlem myopathy, hyperCKemia, and Type 1 fiber predominance on muscle biopsy. One patient who was homozygous for this variant also harbored a pathogenic variant in a separate gene; however, segregation studies could not be completed (PMID: 30706156, 32403337, 38155714); Reported previously in patients with with suspected limb girdle muscular dystrophy (PMID: 34720847, 30564623); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35239206, 26247046, 20576434, 28688748, 29970176, 20976770, 34426522, 33726816, 33596003, 33749658, 32528171, 30487145, 32448721, 32403337, 30564623, 37470033, 36779064, 30706156, 34720847, 37526466, 38127101, 38155714, 36964972, 33441455, 37273706)

#	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		not provided	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449836.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807700.1

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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001920503.1

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

From CeGaT Center for Human Genetics Tuebingen, SCV001962365.21

#	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

From Revvity Omics, Revvity, SCV003829720.2

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197627.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001807700	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None	Uncertain significance	germline	clinical testing
SCV001920503	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None	Uncertain significance	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001807700

Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

Uncertain significance

germline

clinical testing

SCV001920503

Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus

See additional submitters