ClinVar Miner

Submissions for variant NM_002890.3(RASA1):c.2603C>T (p.Pro868Leu) (rs138785106)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000285687 SCV000458987 likely benign Capillary malformation-arteriovenous malformation 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000343253 SCV000458988 likely benign Parkes Weber syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV001034623 SCV000552994 uncertain significance Capillary malformation-arteriovenous malformation 2020-06-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 868 of the RASA1 protein (p.Pro868Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs138785106, ExAC 0.01%). This variant has not been reported in the literature in individuals with RASA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 354525). 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: Tolerated; 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.
GeneDx RCV000681077 SCV000808531 uncertain significance not provided 2018-01-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RASA1 gene. Although the P868L variant has not been published as pathogenic or been reported as benign to our knowledge, it has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000552994.1; Landrum et al., 2016). This variant is observed in 15/125,660 alleles (0.012%) from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This nucleotide substitution (c.2603 C>T) occurs at the last nucleotide of exon 19, a position at which nucleotide substitutions commonly result in abnormal gene splicing (Buratti et al., 2007). Nevertheless, several in silico splice predictions models predict that the c.2603 C>T substitution does not cause abnormal gene splicing. Additionally, although the P868L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.

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