ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.617G>C (p.Gly206Ala) (rs201393380)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756080 SCV000883796 likely benign not provided 2018-03-02 criteria provided, single submitter clinical testing The ENG c.617G>C; p.Gly206Ala variant (rs201393380), is reported in the literature in an individual with features of HHT but not a definitive diagnosis (Mallet 2015), and the variant did not co-segregate with disease in this family. Functional studies of the variant protein show normal localization to the cell surface and a normal BMP9 response (Mallet 2015). This variant is reported in ClinVar (Variation ID: 407133). It is found in the African population with an allele frequency of 0.3% (28/8684 alleles) in the Genome Aggregation Database. The glycine at codon 206 is well conserved, but computational algorithms (SIFT: Damaging, PolyPhen2: Benign) predict conflicting effects of this variant on the protein. Based on available information, this variant is considered likely benign. REFERENCES Mallet C et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet. 2015 Feb 15;24(4):1142-54.
Invitae RCV000463780 SCV000546127 uncertain significance Hereditary hemorrhagic telangiectasia 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 206 of the ENG protein (p.Gly206Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. While this variant is present in population databases (rs201393380), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual with some clinical features consistent with hereditary hemorrhagic telangiectasia, but is said to not segregate with disease in this family (PMID: 25312062). However, the data for the family studies is not included so the significance of this report is uncertain. Experimental studies have shown that this missense change had normal activity in a BMP9 response assay (PMID: 25312062). In summary, this is a rare missense variant this is reported to retain normal functional activity in vitro and did not segregate with disease in a single family. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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