Submissions for variant NM_022132.5(MCCC2):c.557_560delinsTTGTCGAGGTAAGTGT (p.Pro186_Asp187delinsLeuValGluValSerVal)

dbSNP: rs797044772

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179521	SCV000231780	likely pathogenic	not provided	2015-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001246928	SCV001420320	uncertain significance	3-methylcrotonyl-CoA carboxylase 2 deficiency	2021-11-06	criteria provided, single submitter	clinical testing	This variant, c.557_560delins16, is a complex sequence change that results in the deletion of 2 amino acids and insertion of 6 amino acid(s) in the MCCC2 protein (p.Pro186_Asp187delinsLeuValGluValSerVal). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of 3MCC deficiency (Invitae). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582674	SCV001821233	uncertain significance	not specified	2021-08-12	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.557_560delinsTTGTCGAGGTAAGTGT (p.Pro186_Asp187delinsLeuValGluValSerVal) results in a deletion of two amino acids from the protein and insertion of six amino acids. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5` donor site. Two predict the variant creates a 3` acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251460 control chromosomes (gnomAD). To our knowledge, no occurrence of c.557_560delins16 in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.