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NM_006493.4(CLN5):c.350A>C (p.His117Pro) AND Neuronal ceroid lipofuscinosis 5

Germline classification:
Likely pathogenic (1 submission)
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:
RCV003388909.1

Allele description [Variation Report for NM_006493.4(CLN5):c.350A>C (p.His117Pro)]

NM_006493.4(CLN5):c.350A>C (p.His117Pro)

Gene:
CLN5:CLN5 intracellular trafficking protein [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q22.3
Genomic location:
Preferred name:
NM_006493.4(CLN5):c.350A>C (p.His117Pro)
HGVS:
  • NC_000013.11:g.76995912A>C
  • NG_009064.1:g.8989A>C
  • NM_001366624.2:c.350A>C
  • NM_006493.4:c.350A>CMANE SELECT
  • NP_001353553.1:p.His117Pro
  • NP_006484.1:p.His166Pro
  • NP_006484.2:p.His117Pro
  • LRG_692t1:c.497A>C
  • LRG_692:g.8989A>C
  • LRG_692p1:p.His166Pro
  • NC_000013.10:g.77570047A>C
  • NM_006493.2:c.497A>C
Protein change:
H117P
Molecular consequence:
  • NM_001366624.2:c.350A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006493.4:c.350A>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Neuronal ceroid lipofuscinosis 5 (CLN5)
Synonyms:
CEROID LIPOFUSCINOSIS, NEURONAL, 5, VARIABLE AGE AT ONSET; Neuronal ceroid lipofuscinosis Finnish variant; NEURONAL CEROID LIPOFUSCINOSIS, LATE INFANTILE, FINNISH VARIANT; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009745; MedGen: C1850442; Orphanet: 168491; Orphanet: 228360; OMIM: 256731

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004100687Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
South Indian Hindugermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences, SCV004100687.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1South Indian Hindu1not providednot providedclinical testing PubMed (1)

Description

A 8-year-old boy born of consanguineous parentage with pre-existing delay in all the developmental milestones presented with poor scholastic performance and myoclonic atonic seizures from the past six months. On examination he had microcephaly, macular degeneration on fundus examination, scoliosis. EEG showed runs of frontocentral dominant spike slow wave discharges in a quasi periodic manner. Imaging showed cerebellar atrophy, T2/FLAIR hypo-intense bilateral thalamus and T2/FLAIR hyper-intensity in bilateral occipital and posterior limb of internal capsule. Axillary skin biopsy sent for electron microscopy showed characteristic curvilinear inclusions and fingerprint profiles in epithelial and myoepithelial cells of glands and in fibroblasts. Curvilinear inclusions were also noted in Schwann cell cytoplasm of an unmyelinated nerve fiber, diagnostic of NCL. The NM_006493.4:c.350A>C variant has been observed in homozygous state in this individual with a matching phenotype, confirming the diagnosis.

Description

The missense variant NM_006493.4:c.350A>C has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The NP_006484.2:p.His117Pro variant is novel (not in any individuals) in 1000 Genomes, in gnomAD as well as in our inhouse database. There is a moderate physicochemical difference between histidine and proline. The p.His117Pro missense variant is predicted to be damaging by both SIFT and PolyPhen2. The histidine residue at codon 117 of CLN5 is conserved in all mammalian species. The nucleotide c.350 in CLN5 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. In addition, the patient's clinical phenotype matches with that of the disorder caused by pathogenic variants in CLN5 gene. For these reasons, this variant has been classified as Likely Pathogenic (PM2 PP3 PP4_Strong).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Nov 4, 2023