ClinVar Miner

Submissions for variant NM_000401.3(EXT2):c.1121C>T (p.Pro374Leu) (rs141035971)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000795903 SCV000371844 likely benign Multiple exostoses type 2 2018-01-12 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx RCV000766600 SCV000576979 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing The P341L variant in the EXT2 gene has been reported previously as heterozygous in an individual with high myopia (Kloss et al., 2017). The P341L variant is observed in 6/10406 (0.06%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P341L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant in the same residue (P341T) has been reported in an individual with multiple osteochondromas (Ishimaru et al., 2016). Therefore, we interpret P341L as a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000763739 SCV000894624 uncertain significance Multiple exostoses type 2; Seizures, scoliosis, and macrocephaly syndrome 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000795903 SCV000935384 uncertain significance Multiple exostoses type 2 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 341 of the EXT2 protein (p.Pro341Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs141035971, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with EXT2-related disease. ClinVar contains an entry for this variant (Variation ID: 134215). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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 RCV000120888 SCV000085056 not provided not specified 2013-09-19 no assertion provided reference population
GenomeConnect, ClinGen RCV000795903 SCV001423440 not provided Multiple exostoses type 2 no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 04-29-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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