Submissions for variant NM_001854.4(COL11A1):c.4222G>A (p.Gly1408Ser)

gnomAD frequency: 0.00026  dbSNP: rs200496207

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000393287	SCV000346387	uncertain significance	Stickler syndrome type 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000368686	SCV000346389	uncertain significance	Fibrochondrogenesis 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000488030	SCV000574780	uncertain significance	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000488030	SCV001570421	likely benign	not provided	2025-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000488030	SCV001772925	uncertain significance	not provided	2024-02-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 25240749)
Fulgent Genetics, Fulgent Genetics	RCV002480062	SCV002785120	uncertain significance	Intervertebral disc disorder; Marshall syndrome; Stickler syndrome type 2; Fibrochondrogenesis 1; Hearing loss, autosomal dominant 37	2021-07-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002519362	SCV003723695	uncertain significance	Inborn genetic diseases	2021-09-28	criteria provided, single submitter	clinical testing	The c.4222G>A (p.G1408S) alteration is located in exon 56 (coding exon 56) of the COL11A1 gene. This alteration results from a G to A substitution at nucleotide position 4222, causing the glycine (G) at amino acid position 1408 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000488030	SCV005197537	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000488030	SCV001918878	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000488030	SCV001960007	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737426	SCV005355639	uncertain significance	COL11A1-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The COL11A1 c.4222G>A variant is predicted to result in the amino acid substitution p.Gly1408Ser. To our knowledge, this variant has not been reported in the literature. This variant affects a Gly residue of the conserved Gly-Xaa-Yaa triple helical domain (amino acid residues 529-1542, www.uniprot.org/uniprotkb/P12107/), where substitutions of glycine are usually pathogenic (Richards et al. 2010. PubMed ID: 20513134; https://www.ncbi.nlm.nih.gov/books/NBK1302/). However, this variant is reported in 0.030% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than expected for a pathogenic variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Autoinflammatory diseases unit, CHU de Montpellier	RCV000393287	SCV005381978	pathogenic	Stickler syndrome type 2	2024-08-21	no assertion criteria provided	clinical testing