NM_003850.3(SUCLA2):c.920C>T (p.Ala307Val) AND Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 14, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000761522.6

Allele description [Variation Report for NM_003850.3(SUCLA2):c.920C>T (p.Ala307Val)]

NM_003850.3(SUCLA2):c.920C>T (p.Ala307Val)

Gene:

SUCLA2:succinate-CoA ligase ADP-forming subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.2

Genomic location:

Preferred name:

NM_003850.3(SUCLA2):c.920C>T (p.Ala307Val)

HGVS:

NC_000013.11:g.47954440G>A
NG_008241.1:g.51888C>T
NM_003850.3:c.920C>TMANE SELECT
NP_003841.1:p.Ala307Val
NP_003841.1:p.Ala307Val
NC_000013.10:g.48528575G>A
NM_003850.2:c.920C>T

Protein change:

A307V

Links:

dbSNP: rs1011464708

NCBI 1000 Genomes Browser:

rs1011464708

Molecular consequence:

NM_003850.3:c.920C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (MTDPS5)
Synonyms:: Encephalomyopathy; Mitochondrial encephalomyopathy aminoacidopathy; MITOCHONDRIAL DNA DEPLETION SYNDROME, ENCEPHALOMYOPATHIC FORM, WITH OR WITHOUT METHYLMALONIC ACIDURIA, AUTOSOMAL RECESSIVE, SUCLA2-RELATED; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012791; MedGen: C2749864; Orphanet: 1933; OMIM: 612073

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000891654	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 30, 2017)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV001139301	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV004284471	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26475597, 27913098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000891654

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 30, 2017)

unknown

curation

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

SCV001139301

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Likely pathogenic
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV004284471

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 14, 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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.

Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, et al.

J Inherit Metab Dis. 2016 Mar;39(2):243-52. doi: 10.1007/s10545-015-9894-9. Epub 2015 Oct 16.

PubMed [citation]

PMID:: 26475597

See all PubMed Citations (4)

Details of each submission

From Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University, SCV000891654.1

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

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

From Mendelics, SCV001139301.1

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

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

From Invitae, SCV004284471.1

#	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 replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 307 of the SUCLA2 protein (p.Ala307Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with succinyl CoA ligase deficiency (PMID: 26475597, 27913098). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 623373). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SUCLA2 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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: May 19, 2024

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