NM_153704.6(TMEM67):c.653G>C (p.Gly218Ala) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 27, 2022
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:: RCV001857955.3

Allele description [Variation Report for NM_153704.6(TMEM67):c.653G>C (p.Gly218Ala)]

NM_153704.6(TMEM67):c.653G>C (p.Gly218Ala)

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.653G>C (p.Gly218Ala)

HGVS:

NC_000008.11:g.93772590G>C
NG_009190.1:g.22747G>C
NM_001142301.1:c.410G>C
NM_153704.6:c.653G>CMANE SELECT
NP_001135773.1:p.Gly137Ala
NP_714915.3:p.Gly218Ala
NP_714915.3:p.Gly218Ala
LRG_688t1:c.653G>C
LRG_688t2:c.410G>C
LRG_688:g.22747G>C
LRG_688p1:p.Gly218Ala
LRG_688p2:p.Gly137Ala
NC_000008.10:g.94784818G>C
NM_153704.5:c.653G>C
NM_153704.6:c.653G>C
NR_024522.2:n.674G>C

Protein change:

G137A

Links:

dbSNP: rs202036490

NCBI 1000 Genomes Browser:

rs202036490

Molecular consequence:

NM_001142301.1:c.410G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_153704.6:c.653G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_024522.2:n.674G>C - 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
SCV002175409	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 27, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19574260, 18327255, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002175409

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 27, 2022)

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

Citations

PubMed

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).

Doherty D, Parisi MA, Finn LS, Gunay-Aygun M, Al-Mateen M, Bates D, Clericuzio C, Demir H, Dorschner M, van Essen AJ, Gahl WA, Gentile M, Gorden NT, Hikida A, Knutzen D, Ozyurek H, Phelps I, Rosenthal P, Verloes A, Weigand H, Chance PF, Dobyns WB, et al.

J Med Genet. 2010 Jan;47(1):8-21. doi: 10.1136/jmg.2009.067249. Epub 2009 Jul 1.

PubMed [citation]

PMID:: 19574260
PMCID:: PMC3501959

Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.

Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, Alfadhel M, Lewis RA, Eyaid W, Banin E, Dollfus H, Beales PL, Badano JL, Katsanis N.

Nat Genet. 2008 Apr;40(4):443-8. doi: 10.1038/ng.97. Epub 2008 Mar 9. Erratum in: Nat Genet. 2008 Jul;40(7):927. Al-Fadhel, Majid [corrected to Alfadhel, Majid].

PubMed [citation]

PMID:: 18327255

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002175409.2

#	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 glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 218 of the TMEM67 protein (p.Gly218Ala). This variant is present in population databases (rs202036490, gnomAD 0.02%). This missense change has been observed in individual(s) with TMEM67-related condtions (PMID: 18327255, 19574260). ClinVar contains an entry for this variant (Variation ID: 449519). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TMEM67 function (PMID: 18327255). 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: Oct 20, 2024

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