NM_032861.4(SERAC1):c.1684+2T>C AND 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003646718.1

Allele description [Variation Report for NM_032861.4(SERAC1):c.1684+2T>C]

NM_032861.4(SERAC1):c.1684+2T>C

Gene:

SERAC1:serine active site containing 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q25.3

Genomic location:

Preferred name:

NM_032861.4(SERAC1):c.1684+2T>C

HGVS:

NC_000006.12:g.158114787A>G
NG_032889.1:g.58494T>C
NM_032861.4:c.1684+2T>CMANE SELECT
NC_000006.11:g.158535819A>G
NR_073096.2:n.1601T>C

Molecular consequence:

NR_073096.2:n.1601T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_032861.4:c.1684+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL)
Synonyms:: 3-METHYLGLUTACONIC ACIDURIA, TYPE VI; MEGDEL syndrome
Identifiers:: MONDO: MONDO:0013875; MedGen: C4040739; Orphanet: 352328; OMIM: 614739

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004466155	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 22683713, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004466155

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 23, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.

Wortmann SB, Vaz FM, Gardeitchik T, Vissers LE, Renkema GH, Schuurs-Hoeijmakers JH, Kulik W, Lammens M, Christin C, Kluijtmans LA, Rodenburg RJ, Nijtmans LG, Grünewald A, Klein C, Gerhold JM, Kozicz T, van Hasselt PM, Harakalova M, Kloosterman W, Barić I, Pronicka E, Ucar SK, et al.

Nat Genet. 2012 Jun 10;44(7):797-802. doi: 10.1038/ng.2325.

PubMed [citation]

PMID:: 22683713

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004466155.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change affects a donor splice site in intron 15 of the SERAC1 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 SERAC1 are known to be pathogenic (PMID: 22683713). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SERAC1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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