Tubulointerstitial kidney disease

Gene: SEC61A1

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 4:09 p.m. | Last Modified: 20 Oct 2020, 4:09 p.m.

Panel Version: 1.11

Green List (high evidence)

We agree there are sufficient cases reported to upgrade to Green.

Created: 23 Jan 2020, 4:12 a.m. | Last Modified: 23 Jan 2020, 4:12 a.m.

Panel Version: 1.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Familial juvenile Hyperuricemic nephropathy-4 MIM 617056

Publications

• 30586318

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval. The reviewers note that 2 variants associated with kidney disease on HGMD (reported by Bolar et al. 2016). Zebrafish model shows that knockdown of sec61a1 results in a phenotype consistent with tubular atrophy. Variants in the gene result in abnormal intracellular localisation and aggregation (IHC of patient derived kidney biopsy) or decreased protein levels (transfection of HEK293 cells). They are also unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 otholog (Bolar et al. 2016)

Created: 8 Mar 2022, 12:04 p.m. | Last Modified: 8 Mar 2022, 12:04 p.m.

Panel Version: 1.16

Comment on list classification: Changing rating from Amber to Green. Two familial cases reported in Bolar publication plus animal model. Further case reported in Groopman.

Created: 23 Mar 2020, 1:14 p.m. | Last Modified: 23 Mar 2020, 1:14 p.m.

Panel Version: 1.9

PMID: 30586318 - Groopman et al 2019 - Patient CKD184 in Table S7 has a heterozygous missense variant p.I428M in SEC61A1. The genetic diagnosis was Hyperuricemic nephropathy familial juvenile 4.

PMID: 27392076 Bolar et al 2016 - report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly). Zebrafish model re-capitulated the phenotype and could not be rescued by mRNA with the pathogenic alleles.

Created: 23 Mar 2020, 1:12 p.m. | Last Modified: 23 Mar 2020, 1:12 p.m.

Panel Version: 1.7

Upgrading review rating to green, the Groopman paper increases the number of cases to 3.

Created: 13 Nov 2019, 12:23 p.m. | Last Modified: 13 Nov 2019, 12:23 p.m.

Panel Version: 1.0

Further case reported in Groopman et al 2019 (PMID: 30586318)

Created: 11 Sep 2019, 12:55 p.m. | Last Modified: 11 Sep 2019, 12:55 p.m.

Panel Version: 1.0

This gene was part of an initial gene list collated by Emma Ashton (NE Thames Regional Genetics laboratory, GOSH NHS Foundation Trust) January 2019 on behalf of the GMS Renal Specialist Test Group.Gene Symbol submitted:SEC61A1;Suggested initial gene rating: Amber;Evidence for inclusion: none provided;Evidence for exclusion:Suggested phenocopy;Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none provided

Created: 2 Feb 2019, 12:48 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Familial juvenile Hyperuricemic nephropathy-4 MIM 617056