ClinVar Miner

Submissions for variant NM_002524.5(NRAS):c.38G>A (p.Gly13Asp)

dbSNP: rs121434596
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157672 SCV000490967 pathogenic not provided 2015-03-30 criteria provided, single submitter clinical testing The G13D variant has been reported as a de novo germline variant in association with autoimmune lymphoproliferative syndrome (ALPS) (Oliveira et al., 2007). In vitro functional studies demonstrated that the presence of the G13D variant resulted in BCL-2-interacting mediator of cell death down-regulation and defective intrinsic mitochondrial apoptosis prominently in lymphocytes, leading to features of ALPS and hematopoietic malignancies (Oliveira et al., 2007). The G13D variant has also been reported as a germline variant in association with dysmorphic features and Juvenile Myelomonocytic Leukemia (JMML) (De Filippi et al., 2009). The G13D variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV001293767 SCV001480520 likely pathogenic Acute megakaryoblastic leukemia in down syndrome 2020-09-01 criteria provided, single submitter clinical testing
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine RCV000144962 SCV003837579 likely pathogenic Autoimmune lymphoproliferative syndrome type 4 2023-01-03 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000022690 SCV005086264 pathogenic Noonan syndrome 6 2024-10-10 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: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with NRAS-related conditions (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Noonan syndrome, caused by germline variants in the NRAS gene, have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0254 - This variant is low level mosaic in DNA extracted from snap frozen skin biopsy. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the variants in this gene most commonly associated with juvenile myelomonocytic leukaemia (JMML) and it has also been reported in somatic tissue associated with other cancers (ClinVar, PMIDs: 17332249, 18375819, 36130886). In addition, it has been regarded as pathogenic in germline tissue (ClinVar) and has been reported de novo in one individual with JMML and features of Noonan syndrome (PMID: 19775298) and in another individual with autoimmune lymphoproliferative syndrome without features of Noonan syndrome (PMID: 17517660). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000014915 SCV000035171 pathogenic Juvenile myelomonocytic leukemia 2011-03-10 no assertion criteria provided literature only
OMIM RCV000022690 SCV000043979 pathogenic Noonan syndrome 6 2011-03-10 no assertion criteria provided literature only
OMIM RCV000144962 SCV000191989 pathogenic Autoimmune lymphoproliferative syndrome type 4 2011-03-10 no assertion criteria provided literature only
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000157672 SCV000207643 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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