Submissions for variant NM_012062.5(DNM1L):c.1084G>A (p.Gly362Ser)

dbSNP: rs886037861

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000239681	SCV001526300	pathogenic	Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1	2018-08-27	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant was previously reported to occur de novo in a patient with neonatal cyanosis and respiratory distress, postnatal microcephaly, developmental delay with scanty spontaneous movement, hypotonia, and pain insensitivity [PMID 26992161].
GeneDx	RCV001557633	SCV001779427	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a dominant negative effect as this variant significantly impaired oxidative growth and reduced respiratory activity (Verrigni et al., 2019); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30801875, 31475481, 32005694, 31785789, 26992161)
Suma Genomics	RCV000239681	SCV001837612	pathogenic	Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001557633	SCV002156393	pathogenic	not provided	2021-03-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects DNM1L protein function (PMID: 30801875). This variant has been observed in individual(s) with DNM1L-related conditions (PMID: 26992161, 30801875, 31475481). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 253262). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 362 of the DNM1L protein (p.Gly362Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine.
OMIM	RCV000239681	SCV000298165	pathogenic	Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1	2016-08-25	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003897583	SCV004716290	pathogenic	DNM1L-related disorder	2023-12-01	no assertion criteria provided	clinical testing	The DNM1L c.1084G>A variant is predicted to result in the amino acid substitution p.Gly362Ser. This variant was reported to have occurred de novo in multiple individuals with DNM1L-related phenotypes (Sheffer et al. 2016. PubMed ID: 26992161; Verrigni et al. 2019. PubMed ID: 30801875; Table S2, Turner et al. 2019. PubMed ID: 31785789; Table S2, Dong et al. 2020. PubMed ID: 32005694). Functional studies showed that this variant impacts protein function (described as p.Gly397Ser in Saccharomyces cerevisiae studies, Verrigni et al. 2019. PubMed ID: 30801875). This variant has not been reported in a large population database, indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (p.Gly362Asp) has also been reported in individuals with DNM1L-related phenotypes (Verrigni et al. 2019. PubMed ID: 30801875; Table S1, Bruel et al. 2019. PubMed ID: 31231135). Taken together, the c.1084G>A (p.Gly362Ser) variant is interpreted as pathogenic.