NM_153704.6(TMEM67):c.370G>A (p.Glu124Lys) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 3, 2024
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:: RCV001859598.6

Allele description [Variation Report for NM_153704.6(TMEM67):c.370G>A (p.Glu124Lys)]

NM_153704.6(TMEM67):c.370G>A (p.Glu124Lys)

Gene:

TMEM67:transmembrane protein 67 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q22.1

Genomic location:

Preferred name:

NM_153704.6(TMEM67):c.370G>A (p.Glu124Lys)

HGVS:

NC_000008.11:g.93758540G>A
NG_009190.1:g.8697G>A
NM_001142301.1:c.-8G>A
NM_153704.6:c.370G>AMANE SELECT
NP_714915.3:p.Glu124Lys
NP_714915.3:p.Glu124Lys
LRG_688t1:c.370G>A
LRG_688t2:c.-8G>A
LRG_688:g.8697G>A
LRG_688p1:p.Glu124Lys
NC_000008.10:g.94770768G>A
NM_153704.5:c.370G>A
NR_024522.2:n.391G>A
Q5HYA8:p.Glu124Lys

Protein change:

E124K

Links:

UniProtKB: Q5HYA8#VAR_076872; dbSNP: rs375824494

NCBI 1000 Genomes Browser:

rs375824494

Molecular consequence:

NM_001142301.1:c.-8G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_153704.6:c.370G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_024522.2:n.391G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Familial aplasia of the vermis
Synonyms:: CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300

Name:: Meckel-Gruber syndrome
Synonyms:: DYSENCEPHALIA SPLANCHNOCYSTICA; Gruber syndrome; Dysencephalia splachnocystica
Identifiers:: MONDO: MONDO:0018921; MedGen: C0265215; OMIM: PS249000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002237730	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 3, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20232449, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002237730

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 3, 2024)

germline

clinical testing

PubMed (2)
[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

Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies.

Iannicelli M, Brancati F, Mougou-Zerelli S, Mazzotta A, Thomas S, Elkhartoufi N, Travaglini L, Gomes C, Ardissino GL, Bertini E, Boltshauser E, Castorina P, D'Arrigo S, Fischetto R, Leroy B, Loget P, Bonnière M, Starck L, Tantau J, Gentilin B, Majore S, Swistun D, et al.

Hum Mutat. 2010 May;31(5):E1319-31. doi: 10.1002/humu.21239.

PubMed [citation]

PMID:: 20232449
PMCID:: PMC2918781

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002237730.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 124 of the TMEM67 protein (p.Glu124Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Joubert syndrome and related disorders (PMID: 20232449). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 284277). 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 expected to disrupt TMEM67 protein function with a positive predictive value of 95%. 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: Sep 29, 2024

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