rs747900252

Positions:

• chr21-46125776-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001849.4(COL6A2):​c.1970-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000714 in 1,610,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Scores: Splicing: ADA: 0.9941
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:2
• Conservation: PhyloP100: -1.44

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 21-46125776-G-A is Pathogenic according to our data. Variant chr21-46125776-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125776-G-A is described in Lovd as [Pathogenic]. Variant chr21-46125776-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-46125776-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1970-9G>A		intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1970-9G>A		intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.1970-9G>A		intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1970-9G>A		intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1970-9G>A		intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1970-9G>A		intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.641-9G>A		intron_variant		3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 27 AN: 247562 Hom.: 0 AF XY: 0.0000816 AC XY: 11 AN XY: 134756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000713 AC: 104 AN: 1458730 Hom.: 0 Cov.: 36 AF XY: 0.0000744 AC XY: 54 AN XY: 725340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2024	Functional studies show this variant affects the deposition and organization of collagen VI in the extracellular matrix, and the collagen VI level is decreased (PMID: 19309692); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21280092, 33441455, 37526466, 32363432, 20882040, 28578317, 25535305, 27447704, 20576434, 24314752, 20976770, 29774307, 30609409, 32065942, 31127727, 33250842, 34426522, 34106991, 19309692, 38374194) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 21, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2021	- -

Bethlem myopathy 1A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change falls in intron 25 of the COL6A2 gene. It does not directly change the encoded amino acid sequence of the COL6A2 protein. This variant is present in population databases (rs747900252, gnomAD 0.04%). This variant has been observed in individual(s) with autosomal recessive COL6A2-related conditions (PMID: 19309692, 20576434, 21280092, 25535305; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265506). Studies have shown that this variant alters COL6A2 gene expression (PMID: 19309692). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19309692, 21280092). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.85). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21280092, 25535305). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000265506 / PMID: 19309692). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Congenital hip dislocation;C0085639:Falls;C0151786:Muscle weakness;C0311394:Difficulty walking;C3279725:Hip flexor weakness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Collagen 6-related myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 03, 2018

The COL6A2 c.1970-9G>A splice region variant has been reported in at least six studies in which it was found in a total of seven affected individuals, including in one in a homozygous state, in five in a compound heterozygous state with a truncating variant on the second allele, and in one in a heterozygous state in whom the second allele was not detected. The individuals were affected with a range of phenotypes from a moderately severe form of Ullrich congenital muscular dystrophy through different intermediate phenotypes to a milder Bethlem myopathy (Martoni et al. 2009; Deconinck et al. 2010; Foley et al. 2011; Quijano-Roy et al. 2014; Deconinck et al. 2015; Stehlíková et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000436 in the Latino population of the Genome Aggregation Database. The c.1970-9G>A variant was shown to create a cryptic splice site in intron 25, leading to a frameshift and premature termination of the protein and reduced transcript levels to 20% of normal (Martoni et al. 2009). RT-PCR experiments in patient fibroblasts showed the presence of some normally spliced transcript (Foley e al. 2011). Studies in patient fibroblast cultures demonstrated that the variant resulted in significantly reduced levels of collagen VI protein, decreased intracellular secretion, and abnormal deposition and organization of the protein in the extracellular matrix (Martoni et al. 2009; Deconinck et al. 2015). Based on the collective evidence, the c.1970-9G>A variant is classified as pathogenic for an autosomal recessive form of collagen type VI-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Ullrich congenital muscular dystrophy 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 04, 2022

The heterozygous c.1970-9G>A variant in COL6A2 was identified by our study, along with a variant of uncertain significance, in 2 unrelated individuals with either Bethlem myopathy 1 or Ullrich congenital muscular dystrophy 1. The variant has been reported in at least 11 individuals of Brazilian, European, and unknown ethnicity with Ullrich congenital muscular dystrophy 1 or Bethlem myopathy 1 (PMID: 27447704, 19309692, 28578317, 32065942, 21280092, 20576434, 25535305, 20976770, 24314752), and has been identified in 0.04% (15/35314) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs747900252). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 265506) as pathogenic by multiple submitters, as likely pathogenic by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, and as likely benign by Illumina Clinical Services Laboratory. In vitro functional studies provide some evidence that the c.1970-9G>A variant may impact protein function (PMID: 19309692, 21280092). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in at least 3 affected homozygotes, in combination with reported likely pathogenic variants, in combination with reported variants of uncertain significance, and in at least 11 individuals with Ullrich congenital muscular dystrophy 1 or Bethlem myopathy 1 increases the likelihood that the c.1970-9G>A variant is pathogenic (VariationID: 497233; PMID: 19309692, 28578317, 32065942, 21280092, 20576434, 25535305, 20976770, 24314752). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PP3 (Richards 2015). -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Qualitative or quantitative defects of collagen 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 07, 2016

The c.1970-9G>A variant in COL6A2 has been reported in 3 individuals (two compou nd heterozygotes who had other disease-causing variants in trans and one homozyg ote) with Ullrich congenital muscular dystrophy (Martoni 2009, Foley 2011, Decon ninck 2014). This variant has also been identified in 7/113354 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s747900252). This frequency is low enough to be consistent with a recessive carr ier frequency. The c.1970-9G>A variant was demonstrated to cause altered splici ng, leading to a frameshift and a truncated or absent protein (Martoni 2009, Fol ey 2011). In summary, this variant meets our criteria to be classified as patho genic for collagen VI-related myopathy in an autosomal recessive manner based up on its segregation in affected individuals, low frequency in controls and functi onal impact. -

Bethlem myopathy Uncertain:1

Uncertain significance, flagged submission

clinical testing

Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences

Oct 19, 2020

28-year-old female, born as a floppy baby with some improvement. At the moment, she has proximal and distal weakness, and myogenic electromyography. -

Ullrich congenital muscular dystrophy 1B Uncertain:1

Uncertain significance, flagged submission

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	22
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 2
DS_AL_spliceai		0.45		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747900252; hg19: chr21-47545690;