Submissions for variant NM_002890.3(RASA1):c.475_476del (p.Leu159fs)

dbSNP: rs797044451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200157	SCV000250643	pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14639529, 29891884, 31263281)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228029	SCV000552991	pathogenic	Capillary malformation-arteriovenous malformation syndrome	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu159Glyfs*20) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of RASA1-related conditions (PMID: 14639529). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 15999). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000200157	SCV000884450	pathogenic	not provided	2018-06-26	criteria provided, single submitter	clinical testing	The RASA1 c.475_476delCT; p.Leu159fs variant (rs797044451), is reported in the literature in one family and two individuals affected with capillary malformations and/or arteriovenous malformations (Eerola 2003 and Revencu 2013). This variant is classified as pathogenic in ClinVar (Variation ID: 15999), and it is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database). This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Truncating, loss-of-function variants in RASA1 are an established mechanism of disease. Therefore, based on available information, this variant is considered pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV003156050	SCV002525591	pathogenic	Gorham-Stout disease	2021-05-14	criteria provided, single submitter	clinical testing	This sequence change deletes two nucleotides in exon 1 of the RASA1 mRNA, leading to a frameshift and insertion of a premature stop codon. This transcript is predicted to undergo nonsense mediated degradation, leading to RASA1 haploinsufficiency. This variant is absent from population databases and present in patient databases (ClinVar Allele ID: 31038). RASA1 c.475_476delCT has been reported in multiple individuals with capillary malformations and/or arteriovenous malformations (PMID: 14639529, PMID: 15917201, PMID: 29891884).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000200157	SCV005199339	pathogenic	not provided	2023-10-26	criteria provided, single submitter	clinical testing
OMIM	RCV000017370	SCV000037642	pathogenic	Capillary malformation-arteriovenous malformation 1	2003-12-01	no assertion criteria provided	literature only