ClinVar Miner

Submissions for variant NM_001371596.2(MFSD8):c.1006G>C (p.Glu336Gln)

gnomAD frequency: 0.00299  dbSNP: rs150418024
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000732335 SCV000241786 benign not provided 2022-03-08 criteria provided, single submitter clinical testing Identified in multiple unrelated individuals with nonsyndromic macular dystrophy or cone dystrophy who also had a pathogenic MFSD8 variant, suggesting E336Q may cause hypomorphic macular dystrophy when in trans with a pathogenic variant (Roosing et al., 2015; Khan et al., 2017; Haer-Wigman et al., 2017); Published functional studies suggest a damaging effect on CLN7 chloride channel characteristics (Wang et al., 2021); This variant is associated with the following publications: (PMID: 27527004, 26681805, 25227500, 27654426, 30215852, 28559085, 28224992, 28586915, 34426522, 30382371, 33546218, 34910516)
Labcorp Genetics (formerly Invitae), Labcorp RCV001080724 SCV000639417 benign Neuronal ceroid lipofuscinosis 7 2024-01-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002316957 SCV000849627 uncertain significance Inborn genetic diseases 2020-08-10 criteria provided, single submitter clinical testing The p.E336Q variant (also known as c.1006G>C), located in coding exon 10 of the MFSD8 gene, results from a G to C substitution at nucleotide position 1006. The glutamic acid at codon 336 is replaced by glutamine, an amino acid with highly similar properties.This alteration has been detected in individuals with maculopathies and cone disorders and is characterized as a hypomorphic variant that only causes cone dysfunction when it is present in combination with a severe MFSD8 variant (Roosing S, Ophthalmology 2015 Jan; 122(1):170-9; Khan KN et al. Invest. Ophthalmol. Vis. Sci., 2017 Jun;58:2906-2914; Haer-Wigman L et al. Eur. J. Hum. Genet., 2017 05;25:591-599). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Eurofins Ntd Llc (ga) RCV000732335 SCV000860283 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000732335 SCV000892401 likely benign not provided 2023-08-01 criteria provided, single submitter clinical testing MFSD8: BS1
Illumina Laboratory Services, Illumina RCV001080724 SCV001307856 uncertain significance Neuronal ceroid lipofuscinosis 7 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509247 SCV002819803 likely benign not specified 2022-12-24 criteria provided, single submitter clinical testing Variant summary: MFSD8 c.1006G>C (p.Glu336Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 282298 control chromosomes (gnomAD), predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MFSD8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.00094), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1006G>C has been reported in the literature as a biallelic genotype in individuals affected with macular dystrophy (e.g. Roosing_2015). These individuals show no signs of neurological involvement, and patients were diagnosed with macular dystrophy at an advanced age compared to those with Neuronal ceroid lipofuscinosis 7 (27-57 years at age of diagnosis as compared to 2-7 years of age for NCL). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). Nine ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, two as likely pathogenic, one as pathogenic, and three as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity RCV000732335 SCV003808803 uncertain significance not provided 2022-06-03 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003917467 SCV004746690 likely benign MFSD8-related disorder 2019-10-01 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).
OMIM RCV000149771 SCV000196584 pathogenic Macular dystrophy with central cone involvement 2015-01-01 flagged submission literature only
Natera, Inc. RCV001272733 SCV001454991 benign Late-infantile neuronal ceroid lipofuscinosis 2019-12-31 no assertion criteria provided clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV000149771 SCV001548111 likely pathogenic Macular dystrophy with central cone involvement 2021-01-30 flagged submission clinical testing

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