Submissions for variant GRCh38/hg38 4q28.2(chr4:127949707-127984521)x0

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003327629	SCV004034279	pathogenic	Neuronal ceroid lipofuscinosis 7	2023-08-24	criteria provided, single submitter	research	A homozygous deletion of exons 1-3 in MFSD8 (NM_001371596.2) was identified by exome sequencing in one individual with neuronal ceroid lipofuscinosis ([GRCh 38] chr4:127949707_127984521x0). These breakpoints have been estimated by exome sequencing only and therefore may not reflect the true breakpoints. Each copy of the variant was inherited from an unaffected heterozygous parent. The patient phenotype is nonspecific, but is consistent with cases described in the literature and/or published databases with overlapping variants. There is partial overlap with the 5’ end of the MFSD8 gene including coding sequence (NMD is expected to occur). This alteration is then predicted to lead to a truncated or absent protein. Loss of function of NGLY1 is an established disease mechanism in autosomal recessive congenital disorder of deglycosylation (https://search.thegencc.org/). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive neuronal ceroid lipofuscinosis. The ACMG/ClinGen evidence codes and points used in this curation are as follows: 1: 0 points, 2: 0.9 points, 3: 0 points, 4-5: 0.15 points; Total: 1.05 points; Riggs 2020 (PMID: 31690835).