Submissions for variant NM_002890.3(RASA1):c.853C>T (p.Arg285Ter)

dbSNP: rs137853218

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017373	SCV002557952	pathogenic	Capillary malformation-arteriovenous malformation 1	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with capillary malformation-arteriovenous malformation 1 (MIM#608354). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in five unrelated individuals with capillary malformation-arteriovenous malformation, including two de novo cases and one family where the variant segregated in several affected members (PMIDs: 29891884, 25040287, 18363760, 24038909). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458336	SCV004176906	pathogenic	Vascular malformation	2023-09-06	criteria provided, single submitter	clinical testing	The RASA1 c.853C>T (p.Arg285Ter) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with vascular malformations (Hershkovitz D et al., PMID: 18363760; Revencu N et al., PMID: 24038909; Weitz NA et al., PMID: 25040287; Wooderchak-Donahue WL et al., PMID: 29891884). This variant has been reported in the ClinVar database as a germline pathogenic variant by one submitter (ClinVar ID: 16001) and in multiple cases in the cancer database CbioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. The RASA1 c.853C>T (p.Arg285Ter) variant causes a premature truncation codon, which is predicted to result in nonsense-mediated decay, and loss of function is the known disease mechanism (Revencu N et al., PMID: 24038909). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the RASA1 c.853C>T (p.Arg285Ter) variant is classified as pathogenic.
Invitae	RCV003764578	SCV004649572	pathogenic	Capillary malformation-arteriovenous malformation syndrome	2023-03-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 16001). This premature translational stop signal has been observed in individual(s) with capillary malformation (PMID: 18363760, 25040287). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg285*) in the RASA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RASA1 are known to be pathogenic (PMID: 24038909). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003894810	SCV004713150	pathogenic	RASA1-related condition	2023-12-28	criteria provided, single submitter	clinical testing	The RASA1 c.853C>T variant is predicted to result in premature protein termination (p.Arg285*). This variant has been reported as segregating with disease in a large kindred with capillary malformations (Hershkovitz et al. 2008. PubMed ID: 18363760) and in other unrelated individuals with capillary malformations (Weitz et al. 2014. PubMed ID: 25040287; Wooderchak-Donahue et al. 2018. PubMed ID: 29891884). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in RASA1 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.
OMIM	RCV000017373	SCV000037645	pathogenic	Capillary malformation-arteriovenous malformation 1	2008-05-01	no assertion criteria provided	literature only