ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.2299G>A (p.Val767Ile)

gnomAD frequency: 0.00012  dbSNP: rs201949664
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000348098 SCV000475347 uncertain significance Joubert syndrome 6 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000405776 SCV000475348 uncertain significance Nephronophthisis 11 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000289258 SCV000475349 uncertain significance Meckel syndrome, type 3 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001296712 SCV001485684 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 767 of the TMEM67 protein (p.Val767Ile). This variant is present in population databases (rs201949664, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. ClinVar contains an entry for this variant (Variation ID: 363923). 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. 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.
Baylor Genetics RCV001334627 SCV001527525 uncertain significance COACH syndrome 1 2018-11-03 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272216 SCV002557734 uncertain significance Ciliopathy 2020-05-25 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine (exon 23). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (39 heterozygotes, 0 homozygotes). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. Located in the Meckelin domain (PDB, DECIPHER and NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. Three VUS reports (ClinVar) and one report as a pathogenic genetic modifier in a Joubert patient (PMID: 28771248). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics RCV002481247 SCV002797642 uncertain significance COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2022-02-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV004022084 SCV004967280 uncertain significance Inborn genetic diseases 2022-09-07 criteria provided, single submitter clinical testing The c.2299G>A (p.V767I) alteration is located in exon 22 (coding exon 22) of the TMEM67 gene. This alteration results from a G to A substitution at nucleotide position 2299, causing the valine (V) at amino acid position 767 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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