Submissions for variant NM_020166.5(MCCC1):c.559T>C (p.Ser187Pro)

gnomAD frequency: 0.00003  dbSNP: rs757362635

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000702398	SCV000831251	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 187 of the MCCC1 protein (p.Ser187Pro). This variant is present in population databases (rs757362635, gnomAD 0.006%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683). ClinVar contains an entry for this variant (Variation ID: 579181). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Eurofins Ntd Llc (ga)	RCV000727584	SCV000854829	uncertain significance	not provided	2017-11-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000702398	SCV000915330	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency	2017-10-19	criteria provided, single submitter	clinical testing	The MCC1 c.559T>C (p.Ser187Pro) missense variant has been reported in three studies which all appear to describe the same individual. The variant was identified in a compound heterozygous state with a second missense variant in an asymptomatic individual who was detected through newborn screening with residual enzyme activity of approximately 12% of wild type (Dantas et al. 2005; Stadler et al. 2006; Grünert et al. 2012). The variant was absent from 150 controls but is reported at a frequency of 0.000039 in the European (non-Finnish) population of the Genome Aggregation Database. The Ser187 residue is in the biotin carboxylation domain of the protein and is highly conserved (Dantas et al. 2005). Based on the limited evidence, the p.Ser187Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003117497	SCV003801153	uncertain significance	not specified	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: MCCC1 c.559T>C (p.Ser187Pro) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251440 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.559T>C has been reported in the literature as a presumably compound heterozygous genotype in at-least one reportedly asymptomatic individual in settings of newborn screening (NBS) for Methylcrotonyl-CoA Carboxylase Deficiency and as a carrier genotype in another newborn screening case (example, Dantas_2005, cited in Grunert_2012, Navarrete_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000702398	SCV002079117	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency	2020-08-30	no assertion criteria provided	clinical testing