ClinVar Miner

Submissions for variant NM_001963.6(EGF):c.47G>C (p.Ser16Thr) (rs200394315)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000271515 SCV000446950 uncertain significance Hypomagnesemia 4, renal 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Arora Lab,Fox Chase Cancer Center RCV000678686 SCV000693861 uncertain significance Hereditary renal cell carcinoma 2018-02-26 no assertion criteria provided research The pSer16Thr variant (rs200394315) was found at heterozygosity in an individual affected by renal cancer, her non-affected sister and their father. In InterVar, the variant is classified as PP2 (supporting pathogenic) for missense in a gene that has a low rate in benign missense variation, and in which missense variants are a common mechanism of disease. In the GnomAD database (Lek et al. 2016), this variant is overrepresented in the Ashkenazi Jewish population with an allele count of 15/10146 versus 69/276870 in the total population. Other variations of residue include Ser16Arg (1303/276890 with over-representation in East Asian and European Finnish) and Ser16Asn (1 case). Based on Signal 4.0, NCBI describes the pre-protein (reference sequence NP_001954.2) as comprising a signal peptide (SP) at amino acids 1-14. In contrast, UniProt for reference sequence P0113 indicates a cleavage of a signal sequence after amino acid 22. For both predictions, an amino acid change at residue 16 plausibly affects insertion of the pro-EGF precursor into the ER, and hence levels of secretion. No evidence of pathogenicity is reported so this variant is interpreted as VUS.

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