NM_017866.6(TMEM70):c.434A>G (p.Tyr145Cys) AND Mitochondrial complex V (ATP synthase) deficiency nuclear type 2

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 20, 2024
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:: RCV000807690.6

Allele description [Variation Report for NM_017866.6(TMEM70):c.434A>G (p.Tyr145Cys)]

NM_017866.6(TMEM70):c.434A>G (p.Tyr145Cys)

Gene:

TMEM70:transmembrane protein 70 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q21.11

Genomic location:

Preferred name:

NM_017866.6(TMEM70):c.434A>G (p.Tyr145Cys)

HGVS:

NC_000008.11:g.73981272A>G
NG_016618.1:g.10131A>G
NM_001040613.3:c.*124A>G
NM_017866.6:c.434A>GMANE SELECT
NP_060336.3:p.Tyr145Cys
NC_000008.10:g.74893507A>G
NM_017866.5:c.434A>G
NR_033334.2:n.614A>G

Protein change:

Y145C

Links:

dbSNP: rs111248269

NCBI 1000 Genomes Browser:

rs111248269

Molecular consequence:

NM_001040613.3:c.*124A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_017866.6:c.434A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_033334.2:n.614A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mitochondrial complex V (ATP synthase) deficiency nuclear type 2
Synonyms:: ENCEPHALOCARDIOMYOPATHY, MITOCHONDRIAL, NEONATAL, DUE TO ATP SYNTHASE DEFICIENCY; MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, TMEM70 TYPE; Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013546; MedGen: C3279699; Orphanet: 1194; OMIM: 614052

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000947756	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005328656	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 20, 2024)	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

SCV000947756

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 25, 2022)

germline

clinical testing

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

SCV005328656

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Sep 20, 2024)

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	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000947756.4

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 145 of the TMEM70 protein (p.Tyr145Cys). This variant is present in population databases (rs111248269, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TMEM70-related conditions. ClinVar contains an entry for this variant (Variation ID: 652182). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

From 3billion, SCV005328656.1

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

Description

The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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