Submissions for variant NM_020166.5(MCCC1):c.2079del (p.Thr693_Val694insTer)

gnomAD frequency: 0.00002  dbSNP: rs119103217

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000729973	SCV000857676	pathogenic	not provided	2017-11-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000002011	SCV001237044	pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val694*) in the MCCC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the MCCC1 protein. This variant is present in population databases (rs119103217, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 11406611, 22642865). ClinVar contains an entry for this variant (Variation ID: 1934). This variant disrupts the C-terminus of the MCCC1 protein. Other variant(s) that disrupt this region (p.Val697Serfs*19) have been observed in individuals with MCCC1-related conditions (PMID: 16010683, 22642865). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000729973	SCV002504081	likely pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 32 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 32778825, 22642865, 11406611)
Baylor Genetics	RCV000002011	SCV004191953	pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2024-02-16	criteria provided, single submitter	clinical testing
OMIM	RCV000002011	SCV000022169	pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2001-06-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001273490	SCV001456577	pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390633	SCV004120725	pathogenic	MCCC1-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The MCCC1 c.2079delA variant is predicted to result in premature protein termination (p.Val694*). This variant has been reported in individuals with autosomal recessive 3-methylcrotonyl-CoA carboxylase deficiency (Holzinger et al 2001. PubMed ID: 11406611; Grünert et al 2012. PubMed ID: 22642865). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in MCCC1 are expected to be pathogenic. This variant is interpreted as pathogenic.