Submissions for variant NM_024596.5(MCPH1):c.664T>C (p.Cys222Arg)

gnomAD frequency: 0.00037  dbSNP: rs41313952

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193214	SCV000247921	uncertain significance	not specified	2014-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000766670	SCV000582151	uncertain significance	not provided	2017-05-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MCPH1 gene. The C222R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The C222R variant is observed in 6/6552 (0.09%) alleles from individuals of Finnish background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C222R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766670	SCV001081601	likely benign	not provided	2025-01-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001161371	SCV001323237	uncertain significance	Microcephaly 1, primary, autosomal recessive	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002517951	SCV003585033	uncertain significance	Inborn genetic diseases	2020-11-10	criteria provided, single submitter	clinical testing	The c.664T>C (p.C222R) alteration is located in exon 7 (coding exon 7) of the MCPH1 gene. This alteration results from a T to C substitution at nucleotide position 664, causing the cysteine (C) at amino acid position 222 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the MCPH1 c.664T>C alteration was observed in 0.04% (118/280498) of total alleles studied, with a frequency of 0.26% (27/10354) in the Ashkenazi Jewish subpopulation. This amino acid position is poorly conserved in available vertebrate species. The p.C222R alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001161371	SCV003810847	uncertain significance	Microcephaly 1, primary, autosomal recessive	2021-06-30	criteria provided, single submitter	clinical testing