Submissions for variant NM_031433.4(MFRP):c.642-2A>G

gnomAD frequency: 0.00006  dbSNP: rs376898612

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593268	SCV000701576	pathogenic	not provided	2016-10-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778307	SCV000914489	uncertain significance	Late-onset retinal degeneration	2018-11-06	criteria provided, single submitter	clinical testing	This variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL 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 for this variant, it 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 and cDNA change. No publications were found based on this search. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of uncertain significance but suspicious for pathogenicity for this disease.
Illumina Laboratory Services, Illumina	RCV000778308	SCV000914490	uncertain significance	Isolated microphthalmia 5	2018-11-06	criteria provided, single submitter	clinical testing	This variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL 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 for this variant, it 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 and cDNA change. No publications were found based on this search. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of uncertain significance but suspicious for pathogenicity for this disease.
Invitae	RCV000778308	SCV002236399	pathogenic	Isolated microphthalmia 5	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the MFRP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MFRP are known to be pathogenic (PMID: 12140190, 15976030, 20361016). This variant is present in population databases (rs376898612, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with microphthalmia (PMID: 33203948). ClinVar contains an entry for this variant (Variation ID: 497208). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.