VCV000253262.12 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 253262 Accession: VCV000253262.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 32731018 (GRCh38) [ NCBI UCSC ] 12: 32883952 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 29, 2016	Oct 8, 2024	Apr 12, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_012062.5:c.1084G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036192.2:p.Gly362Ser	missense
NM_001278464.2:c.1123G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001265393.1:p.Gly375Ser	missense
NM_001278463.2:c.1084G>A	NP_001265392.1:p.Gly362Ser	missense
NM_001278465.2:c.1123G>A	NP_001265394.1:p.Gly375Ser	missense
NM_001278466.2:c.475G>A	NP_001265395.1:p.Gly159Ser	missense
NM_001330380.2:c.1123G>A	NP_001317309.1:p.Gly375Ser	missense
NM_005690.5:c.1084G>A	NP_005681.2:p.Gly362Ser	missense
NM_012062.4:c.1084G>A
NM_012063.4:c.1084G>A	NP_036193.2:p.Gly362Ser	missense
NC_000012.12:g.32731018G>A
NC_000012.11:g.32883952G>A
NG_012219.1:g.56816G>A
	O00429:p.Gly362Ser

... more HGVS ... less HGVS

Protein change

G362S, G375S, G159S

Other names

Canonical SPDI

NC_000012.12:32731017:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs886037861 ClinGen: CA10586276 UniProtKB: O00429#VAR_076317 OMIM: 603850.0003 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DNM1L		-	-	GRCh38 GRCh37	689	762

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 27, 2018	RCV000239681.5
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 12, 2022	RCV001557633.8
DNM1L-related disorder	Pathogenic (1)	no assertion criteria provided	Dec 1, 2023	RCV003897583.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001526300.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (1) PubMed: 26992161 Comment: 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 … (more) 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]. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Suma Genomics Accession: SCV001837612.1 First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021
Pathogenic (Apr 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001779427.3 First in ClinVar: Aug 13, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Mar 24, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002156393.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 30801875‚ 26992161‚ 31475481 Comment: 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 … (more) 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. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 25, 2016)	no assertion criteria provided Method: literature only	ENCEPHALOPATHY DUE TO DEFECTIVE MITOCHONDRIAL AND PEROXISOMAL FISSION 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000298165.1 First in ClinVar: Aug 29, 2016 Last updated: Aug 29, 2016	Publications: PubMed (1) PubMed: 26992161 Comment on evidence: In a 2-year-old boy, born of unrelated Arab parents, with encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Sheffer et al. (2016) identified … (more) In a 2-year-old boy, born of unrelated Arab parents, with encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1; 614388), Sheffer et al. (2016) identified a de novo heterozygous c.1084G-A transition (c.1084G-A, NM_001278463) in the DNM1L gene, resulting in a gly362-to-ser (G362S) substitution at a highly conserved residue in the middle domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 132) database or an in-house database. Transfection of the mutation into fibroblasts caused significantly altered mitochondrial morphology, with bulky clusters of mitochondria concentrated in a small area of the cell and absent in the remaining part. The cells were also 60% smaller than control cells. Patient fibroblasts showed abnormally elongated mitochondria, mitochondrial complex IV deficiency, decreased ATP production, and decreased oxygen consumption; peroxisomes appeared to be unaffected. (less)
Pathogenic (Dec 01, 2023)	no assertion criteria provided Method: clinical testing	DNM1L-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004716290.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)

Comment:

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].

Comment:

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)

Comment:

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. For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
De novo pathogenic DNM1L variant in a patient diagnosed with atypical hereditary sensory and autonomic neuropathy.	Tarailo-Graovac M	Molecular genetics & genomic medicine	2019	PMID: 31475481
Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy.	Verrigni D	Human mutation	2019	PMID: 30801875
Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function.	Sheffer R	American journal of medical genetics. Part A	2016	PMID: 26992161

Text-mined citations for rs886037861 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886037861 ...