Submissions for variant NM_005188.4(CBL):c.1942A>C (p.Ser648Arg)

gnomAD frequency: 0.00035  dbSNP: rs143264567

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000361702	SCV000330103	uncertain significance	not provided	2017-11-20	criteria provided, single submitter	clinical testing	The S648R variant in the CBL gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S648R variant is observed in 22/24,026 (0.09%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The S648R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret S648R as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001089369	SCV000817535	likely benign	RASopathy	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192739	SCV001361041	likely benign	not specified	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: CBL c.1942A>C (p.Ser648Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251458 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 320 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBL causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1942A>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
New York Genome Center	RCV000361702	SCV001468868	uncertain significance	not provided	2019-07-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813442	SCV002060493	benign	Noonan syndrome and Noonan-related syndrome	2018-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021064	SCV003686039	likely benign	Cardiovascular phenotype	2022-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.