Submissions for variant NM_005188.4(CBL):c.2312A>T (p.Asp771Val)

gnomAD frequency: 0.00010  dbSNP: rs199788586

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719718	SCV000057273	likely benign	not provided	2020-10-09	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038356	SCV000062028	uncertain significance	not specified	2016-08-23	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Asp771Val var iant in CBL has been identified by our laboratory in 2 Caucasian individuals wit h clinical features of a RASopathy disorder, both of whom also carried a disease -causing variant in another gene sufficient to explain their disease. This varia nt has been identified in 13/66740 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199788586). Computati onal prediction tools and conservation analysis suggest that this variant may no t impact the protein, though this information is not predictive enough to rule o ut pathogenicity. In summary, while the clinical significance of the p.Asp771Val variant is uncertain, the presence of this variant in combination with a report ed pathogenic variant suggests that it is more likely to be benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552056	SCV000659111	likely benign	RASopathy	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038356	SCV001362202	likely benign	not specified	2021-06-14	criteria provided, single submitter	clinical testing	Variant summary: CBL c.2312A>T (p.Asp771Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251462 control chromosomes. The observed variant frequency is approximately 37 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 benign. To our knowledge, no occurrence of c.2312A>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory has re-classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813230	SCV002060756	uncertain significance	Noonan syndrome and Noonan-related syndrome	2020-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018707	SCV003692349	uncertain significance	Cardiovascular phenotype	2022-12-28	criteria provided, single submitter	clinical testing	The c.2312A>T (p.D771V) alteration is located in exon 15 (coding exon 15) of the CBL gene. This alteration results from a A to T substitution at nucleotide position 2312, causing the aspartic acid (D) at amino acid position 771 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV001719718	SCV004129486	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	CBL: BP4, BS1
PreventionGenetics, part of Exact Sciences	RCV004532482	SCV004730625	likely benign	CBL-related disorder	2022-08-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).