Submissions for variant NM_031433.4(MFRP):c.1014C>A (p.Ser338Arg)

gnomAD frequency: 0.00126  dbSNP: rs145319149

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153493	SCV000203011	uncertain significance	not provided	2013-08-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000388917	SCV000367982	uncertain significance	Retinal degeneration	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000691291	SCV000367983	uncertain significance	Isolated microphthalmia 5	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.
Invitae	RCV000691291	SCV000819043	uncertain significance	Isolated microphthalmia 5	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 338 of the MFRP protein (p.Ser338Arg). This variant is present in population databases (rs145319149, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MFRP-related conditions. ClinVar contains an entry for this variant (Variation ID: 167294). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MFRP protein function. 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.
Illumina Laboratory Services, Illumina	RCV001104223	SCV001261073	likely benign	Late-onset retinal degeneration	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
PreventionGenetics, part of Exact Sciences	RCV004532728	SCV004743067	likely benign	MFRP-related disorder	2022-02-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000153493	SCV001967581	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000153493	SCV001979153	uncertain significance	not provided		no assertion criteria provided	clinical testing