NM_001258392.3(CLPB):c.259A>T (p.Thr87Ser) AND 3-methylglutaconic aciduria, type VIIB

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 7, 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:: RCV001331420.7

Allele description [Variation Report for NM_001258392.3(CLPB):c.259A>T (p.Thr87Ser)]

NM_001258392.3(CLPB):c.259A>T (p.Thr87Ser)

Genes:

LOC130006336:ATAC-STARR-seq lymphoblastoid active region 5191 [Gene]
CLPB:ClpB family mitochondrial disaggregase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

NM_001258392.3(CLPB):c.259A>T (p.Thr87Ser)

HGVS:

NC_000011.10:g.72434216T>A
NG_042130.2:g.5469A>T
NM_001258392.3:c.259A>TMANE SELECT
NM_001258393.3:c.259A>T
NM_001258394.3:c.17A>T
NM_030813.6:c.259A>T
NP_001245321.1:p.Thr87Ser
NP_001245322.1:p.Thr87Ser
NP_001245323.1:p.His6Leu
NP_110440.1:p.Thr87Ser
LRG_1338t1:c.259A>T
LRG_1338:g.5469A>T
LRG_1338p1:p.Thr87Ser
NC_000011.9:g.72145260T>A
NM_030813.4:c.259A>T

Protein change:

H6L

Links:

dbSNP: rs960976552

NCBI 1000 Genomes Browser:

rs960976552

Molecular consequence:

NM_001258392.3:c.259A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258393.3:c.259A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258394.3:c.17A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_030813.6:c.259A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: 3-methylglutaconic aciduria, type VIIB (MGCA7B)
Synonyms:: 3-methylglutaconic aciduria with cataracts, neurologic involvement and neutropenia; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia
Identifiers:: MONDO: MONDO:0014561; MedGen: C5676893; Orphanet: 445038; OMIM: 616271

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001523456	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 10, 2019)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002221695	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 7, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001523456

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 10, 2019)

maternal

clinical testing

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

SCV002221695

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 7, 2023)

germline

clinical testing

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

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	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Baylor Genetics, SCV001523456.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002221695.3

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

Description

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1029982). This variant has not been reported in the literature in individuals affected with CLPB-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 87 of the CLPB protein (p.Thr87Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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