NM_032861.4(SERAC1):c.262_265dup (p.Gly89fs) AND 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Apr 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000190622.8

Allele description [Variation Report for NM_032861.4(SERAC1):c.262_265dup (p.Gly89fs)]

NM_032861.4(SERAC1):c.262_265dup (p.Gly89fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

6q25.3

Genomic location:

Preferred name:

NM_032861.4(SERAC1):c.262_265dup (p.Gly89fs)

Other names:

NM_032861.3:c.262_265dupCATG

HGVS:

NC_000006.12:g.158150453_158150456dup
NG_032889.1:g.22825_22828dup
NM_032861.4:c.262_265dupMANE SELECT
NP_116250.3:p.Gly89fs
NC_000006.11:g.158571484_158571485insCATG
NC_000006.11:g.158571485_158571488dup
NR_073096.2:n.386_389dup

Protein change:

G89fs

Links:

dbSNP: rs797045105

NCBI 1000 Genomes Browser:

rs797045105

Molecular consequence:

NM_032861.4:c.262_265dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_073096.2:n.386_389dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV000245658	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Sep 28, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003314997	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33613893, 22683713, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000245658

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Sep 28, 2014)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003314997

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 24, 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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Identification of the rs797045105 in the SERAC1 Gene by Whole-exome Sequencing in a Patient Suspicious of MEGDEL Syndrome.

Zamani M, Seifi T, Zeighami J, Mazaheri N, Jahangirnezhad E, Gholamzadeh M, Sedaghat A, Shariati G, Galehdari H.

Basic Clin Neurosci. 2020 Jul-Aug;11(4):549-556. doi: 10.32598/bcn.9.10.455. Epub 2020 Jul 1.

PubMed [citation]

PMID:: 33613893
PMCID:: PMC7878045

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq, SCV000245658.1

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

Description

The p.Gly89AlafsX32 variant in SERAC1 has not been previously reported in individuals with disease or in large population studies. This variant is predicted to cause a frameshift, which would alter the protein’s amino acid sequence beginning at position 89 and lead to a premature termination codon 32 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SERAC1 gene is an established disease mechanism in individuals with 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome. In summary, this variant is likely pathogenic for 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome in an autosomal recessive manner, though additional data is required to prove the predicted impact on the gene.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003314997.2

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

Description

This premature translational stop signal has been observed in individual(s) with 3-methylglutaconic aciduria (PMID: 33613893). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly89Alafs*32) in the SERAC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SERAC1 are known to be pathogenic (PMID: 22683713). ClinVar contains an entry for this variant (Variation ID: 208610). 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 disrupt the consensus splice site.

#	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: Sep 29, 2024

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