NM_015072.5(TTLL5):c.1627G>A (p.Glu543Lys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001093124.22

Allele description [Variation Report for NM_015072.5(TTLL5):c.1627G>A (p.Glu543Lys)]

NM_015072.5(TTLL5):c.1627G>A (p.Glu543Lys)

Gene:

TTLL5:tubulin tyrosine ligase like 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q24.3

Genomic location:

Preferred name:

NM_015072.5(TTLL5):c.1627G>A (p.Glu543Lys)

HGVS:

NC_000014.9:g.75764691G>A
NG_016974.1:g.108484G>A
NM_015072.5:c.1627G>AMANE SELECT
NP_055887.3:p.Glu543Lys
NC_000014.8:g.76231034G>A
NM_015072.4:c.1627G>A
Q6EMB2:p.Glu543Lys

Protein change:

E543K; GLU543LYS

Links:

UniProtKB: Q6EMB2#VAR_071327; OMIM: 612268.0005; dbSNP: rs199882533

NCBI 1000 Genomes Browser:

rs199882533

Molecular consequence:

NM_015072.5:c.1627G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001249954	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Sep 1, 2017)	germline	clinical testing	Citation Link,
SCV001578007	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24791901, 28173158, 27162334, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001249954

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Sep 1, 2017)

germline

clinical testing

Citation Link,

SCV001578007

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (4)
[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	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy.

Sergouniotis PI, Chakarova C, Murphy C, Becker M, Lenassi E, Arno G, Lek M, MacArthur DG; UCL-Exomes Consortium., Bhattacharya SS, Moore AT, Holder GE, Robson AG, Wolfrum U, Webster AR, Plagnol V.

Am J Hum Genet. 2014 May 1;94(5):760-9. doi: 10.1016/j.ajhg.2014.04.003.

PubMed [citation]

PMID:: 24791901
PMCID:: PMC4067560

Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility.

Bedoni N, Haer-Wigman L, Vaclavik V, Tran VH, Farinelli P, Balzano S, Royer-Bertrand B, El-Asrag ME, Bonny O, Ikonomidis C, Litzistorf Y, Nikopoulos K, Yioti GG, Stefaniotou MI, McKibbin M, Booth AP, Ellingford JM, Black GC, Toomes C, Inglehearn CF, Hoyng CB, Bax N, et al.

Hum Mol Genet. 2016 Oct 15;25(20):4546-4555. doi: 10.1093/hmg/ddw282.

PubMed [citation]

PMID:: 28173158

See all PubMed Citations (4)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001249954.23

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Invitae, SCV001578007.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 543 of the TTLL5 protein (p.Glu543Lys). This variant is present in population databases (rs199882533, gnomAD 0.06%). This missense change has been observed in individuals with retinal dystrophy (PMID: 24791901, 28173158). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 139517). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TTLL5 protein function. Experimental studies have shown that this missense change affects TTLL5 function (PMID: 27162334). For these reasons, this variant has been classified as Pathogenic.

#	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: Jul 29, 2024

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