NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser) AND COACH syndrome 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 1, 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:: RCV002283466.2

Allele description [Variation Report for NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)]

NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)

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.725A>G (p.Asn242Ser)

HGVS:

NC_000008.11:g.93780603A>G
NG_009190.1:g.30760A>G
NM_001142301.1:c.482A>G
NM_153704.6:c.725A>GMANE SELECT
NP_001135773.1:p.Asn161Ser
NP_714915.3:p.Asn242Ser
NP_714915.3:p.Asn242Ser
LRG_688t1:c.725A>G
LRG_688t2:c.482A>G
LRG_688:g.30760A>G
LRG_688p1:p.Asn242Ser
LRG_688p2:p.Asn161Ser
NC_000008.10:g.94792831A>G
NM_153704.5:c.725A>G
NR_024522.2:n.746A>G
p.Asn242Ser

Protein change:

N161S

Links:

dbSNP: rs775883520

NCBI 1000 Genomes Browser:

rs775883520

Molecular consequence:

NM_001142301.1:c.482A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_153704.6:c.725A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_024522.2:n.746A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: COACH syndrome 1
Identifiers:: MONDO: MONDO:0800103; MedGen: C5435651; Orphanet: 1454; OMIM: 216360

Recent activity

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DDB1- and CUL4-associated factor 6 isoform X4 [Homo sapiens]
DDB1- and CUL4-associated factor 6 isoform X4 [Homo sapiens]
gi|2462511380|ref|XP_054193635.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002572798	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19574260, 23559409, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002572798

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 1, 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	yes	1	not provided	not provided	1	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

Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.

Halbritter J, Porath JD, Diaz KA, Braun DA, Kohl S, Chaki M, Allen SJ, Soliman NA, Hildebrandt F, Otto EA; GPN Study Group..

Hum Genet. 2013 Aug;132(8):865-84. doi: 10.1007/s00439-013-1297-0. Epub 2013 Apr 5.

PubMed [citation]

PMID:: 23559409
PMCID:: PMC4643834

See all PubMed Citations (3)

Details of each submission

From 3billion, SCV002572798.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000216826). Different missense changes at the same codon (p.Asn242Lys, p.Asn242Thr) have been reported to be associated with TMEM67 -related disorder (PMID: 19574260 , 23559409). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Oct 20, 2024

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