Submissions for variant NM_000095.3(COMP):c.968A>G (p.Asn323Ser)

gnomAD frequency: 0.00004  dbSNP: rs367812050

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001751693	SCV001997460	uncertain significance	not provided	2019-12-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001751693	SCV004278386	uncertain significance	not provided	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 323 of the COMP protein (p.Asn323Ser). This variant is present in population databases (rs367812050, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COMP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049010). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COMP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354542	SCV001549186	uncertain significance	Multiple epiphyseal dysplasia type 1		no assertion criteria provided	clinical testing	The COMP p.N323S variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs367812050) and in control databases in 10 of 249136 chromosomes at a frequency of 0.00004014 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.N323 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357397	SCV001552863	uncertain significance	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome		no assertion criteria provided	clinical testing	The COMP p.N323S variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs367812050) and in control databases in 10 of 249136 chromosomes at a frequency of 0.00004014 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.N323 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.