Submissions for variant NM_024596.5(MCPH1):c.2108G>A (p.Arg703His)

gnomAD frequency: 0.00013  dbSNP: rs370275760

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153482	SCV000202993	uncertain significance	not provided	2014-04-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000766031	SCV000474626	uncertain significance	Microcephaly 1, primary, autosomal recessive	2018-01-13	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.
Fulgent Genetics, Fulgent Genetics	RCV000766031	SCV000897470	uncertain significance	Microcephaly 1, primary, autosomal recessive	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000153482	SCV001805101	uncertain significance	not provided	2021-12-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000153482	SCV002148915	uncertain significance	not provided	2022-04-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 703 of the MCPH1 protein (p.Arg703His). This variant is present in population databases (rs370275760, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MCPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167286). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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.
Ambry Genetics	RCV002514958	SCV003688026	uncertain significance	Inborn genetic diseases	2021-09-16	criteria provided, single submitter	clinical testing	The c.2108G>A (p.R703H) alteration is located in exon 11 (coding exon 11) of the MCPH1 gene. This alteration results from a G to A substitution at nucleotide position 2108, causing the arginine (R) at amino acid position 703 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.