Submissions for variant NM_080680.3(COL11A2):c.889G>A (p.Gly297Ser)

gnomAD frequency: 0.00012  dbSNP: rs139116571

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724260	SCV000232326	uncertain significance	not provided	2014-10-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223442	SCV000271609	uncertain significance	not specified	2015-06-22	criteria provided, single submitter	clinical testing	The p.Gly297Ser variant in COL11A2 has not been previously reported in individua ls with hearing loss, but has been identified in 1/6758 European American chromo somes by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs139116571). Computational prediction tools and conservation analyses su ggest that the p.Gly297Ser variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. In summary, the clini cal significance of the p.Gly297Ser variant is uncertain.
GeneDx	RCV000724260	SCV000491063	uncertain significance	not provided	2025-02-11	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25633957)
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678342	SCV000804406	uncertain significance	Otospondylomegaepiphyseal dysplasia, autosomal dominant	2017-10-03	criteria provided, single submitter	provider interpretation	This 9 year old female has severe intellectual disability, growth and feeding problems requiring a G-tube as an infant, a repaired cleft palate, short stature (4 SD below average), microcephaly, scoliosis, deviated septum, widely set nipples, curved 4th and 5th digits bilaterally, recurrent nosebleeds, and possible hearing loss. Dysmorphic facial features include midface depression, prominent forehead, low set and posteriorly rotated ears, and micrognathia. Benign pulmonary artery branch stenosis and a small PFO were noted on echocardiogram, and an abnormal brain MRI done at 8 years of age showed scattered, non-enhancing, non-specific punctate predominately subcortical T2 hyperintensities with mild-moderate cerebral volume loss. Her bone age at 8 years, 1 month was essentially normal (0.3 SD below mean). Tympanograms were done at 7 years of age and were within normal limits bilaterally with OAEs at fail/refer results bilaterally. The p.G297S variant was maternally inherited and is present in gnomAD, occurring 0.01% in the Latino population and 0.02% in European non-Finnish. Computational model predictions are inconsistent. A second VUS was also identified in COLL11A2, inheritance is unknown.
Fulgent Genetics, Fulgent Genetics	RCV000764647	SCV000895756	uncertain significance	Autosomal recessive nonsyndromic hearing loss 53; Autosomal dominant nonsyndromic hearing loss 13; Otospondylomegaepiphyseal dysplasia, autosomal recessive; Otospondylomegaepiphyseal dysplasia, autosomal dominant; Fibrochondrogenesis 2	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253705	SCV001429554	uncertain significance	Autosomal dominant nonsyndromic hearing loss 13	2017-02-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724260	SCV001571174	likely benign	not provided	2024-11-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277425	SCV002567104	uncertain significance	Connective tissue disorder	2019-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748639	SCV005363980	uncertain significance	COL11A2-related disorder	2024-03-06	no assertion criteria provided	clinical testing	The COL11A2 c.889G>A variant is predicted to result in the amino acid substitution p.Gly297Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.