Submissions for variant NM_000127.3(EXT1):c.122G>A (p.Ser41Asn)

gnomAD frequency: 0.00009  dbSNP: rs199862937

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001205167	SCV001376408	uncertain significance	Multiple congenital exostosis	2023-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 41 of the EXT1 protein (p.Ser41Asn). 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 missense change has been observed in individual(s) with multiple osteochondromas (PMID: 18373409). ClinVar contains an entry for this variant (Variation ID: 134197). 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 EXT1 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.
ITMI	RCV000120870	SCV000085038	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356540	SCV001551741	uncertain significance	not provided		no assertion criteria provided	clinical testing	The EXT1 p.S41N variant was identified in an individual with multiple osteochondromas; however, this variant did not cosegregate with disease in 4 affected family members (Leube_2008_PMID: 18373409). The variant was not identified in COSMIC, but it was identified in dbSNP (ID: rs199862937) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 28 of 282452 chromosomes at a frequency of 0.00009913 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.S41 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 deleterious effect on 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.