Submissions for variant NM_001852.4(COL9A2):c.1242del (p.Gly415fs)

dbSNP: rs756694568

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778980	SCV000915411	uncertain significance	Stickler syndrome, type 5	2017-04-28	criteria provided, single submitter	clinical testing	The COL9A2 c.1242delC (p.Gly415GlufsTer116) variant results in a frameshift, and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it 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 and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive Stickler syndrome.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873178	SCV002208316	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly415Glufs*116) in the COL9A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL9A2 are known to be pathogenic (PMID: 21671392, 33356723). 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 variant has not been reported in the literature in individuals affected with COL9A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 632106). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001873178	SCV002821022	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	COL9A2: PVS1, PM2, PM3:Supporting
GeneDx	RCV001873178	SCV003842596	likely pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003396351	SCV004103101	uncertain significance	COL9A2-related disorder	2023-09-05	criteria provided, single submitter	clinical testing	The COL9A2 c.1242delC variant is predicted to result in a frameshift and premature protein termination (p.Gly415Glufs*116). This variant was reported in the homozygous state in an individual with clinical features consistent with Stickler syndrome. The described patient, who had consanguineous parents, also had features consistent with an immune disorder and was homozygous for possibly causative variants in both AK2 and ATM (Ichikawa et al. 2020. PubMed ID: 32532877). This variant is reported in 0.015% of alleles in individuals of African descent in gnomAD, although gnomAD quality metrics indicate the data quality may be low at this site and therefore allele frequencies should be interpreted with caution (http://gnomad.broadinstitute.org/variant/1-40770036-CG-C). While we suspect this variant may be pathogenic for autosomal recessive COL9A2-related Stickler syndrome, it is less likely to be causative for autosomal dominant multiple epiphyseal dysplasia, which is typically associated with variants impacting nucleotide c.186 or the adjacent splice donor site (Human Gene Mutation Database, HGMD).
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783853	SCV005397448	likely pathogenic	Epiphyseal dysplasia, multiple, 2	2022-10-21	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide deletion (delC) at coding position 1242 in the COL9A2 gene which results in an early termition sigl 116 codons downstream from the frameshift at residue 415. Because this termition occurs in exon 28 of 32, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or a loss of COL9A2 expression due to nonsense-mediated decay. This is a previously reported variant (ClinVar) that has been observed in homozygous state in a patient with suspected Stickler syndrome type V (PMID: 32532877). This variant is present in 20/227864 alleles (0.008%) in the gnomAD control population dataset. Recent studies have demonstrated that loss-of-function variants in COL9A2 are associated with a recessive form of Stickler syndrome. Given the available information, we consider this a likely pathogenic variant. ACMG Criteria: PM3, PVS1