NM_153704.6(TMEM67):c.245C>G (p.Pro82Arg) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 31, 2023
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:: RCV003765306.2

Allele description [Variation Report for NM_153704.6(TMEM67):c.245C>G (p.Pro82Arg)]

NM_153704.6(TMEM67):c.245C>G (p.Pro82Arg)

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.245C>G (p.Pro82Arg)

HGVS:

NC_000008.11:g.93755799C>G
NG_009190.1:g.5956C>G
NM_001142301.1:c.-62+662C>G
NM_153704.6:c.245C>GMANE SELECT
NP_714915.3:p.Pro82Arg
NP_714915.3:p.Pro82Arg
LRG_688t1:c.245C>G
LRG_688t2:c.-62+662C>G
LRG_688:g.5956C>G
LRG_688p1:p.Pro82Arg
NC_000008.10:g.94768027C>G
NC_000008.10:g.94768027C>G
NM_153704.5:c.245C>G
NR_024522.2:n.266C>G
Q5HYA8:p.Pro82Arg

Protein change:

P82R

Links:

UniProtKB: Q5HYA8#VAR_063783; dbSNP: rs772437766

NCBI 1000 Genomes Browser:

rs772437766

Molecular consequence:

NM_001142301.1:c.-62+662C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_153704.6:c.245C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_024522.2:n.266C>G - 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
SCV004570134	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19574260, 29568536, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004570134

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 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

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

Cerebellar cognitive affective syndrome: insights from Joubert syndrome.

Hickey CL, Sherman JC, Goldenberg P, Kritzer A, Caruso P, Schmahmann JD, Colvin MK.

Cerebellum Ataxias. 2018;5:5. doi: 10.1186/s40673-018-0085-y.

PubMed [citation]

PMID:: 29568536
PMCID:: PMC5861599

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004570134.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro82 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been observed in individuals with TMEM67-related conditions (PMID: 19574260, 29568536), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 217714). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 19574260, 29568536). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 82 of the TMEM67 protein (p.Pro82Arg).

#	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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