NM_001371986.1(UNC80):c.5296C>T (p.Pro1766Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 5, 2022
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:: RCV001753625.8

Allele description [Variation Report for NM_001371986.1(UNC80):c.5296C>T (p.Pro1766Ser)]

NM_001371986.1(UNC80):c.5296C>T (p.Pro1766Ser)

Genes:

LOC126806490:P300/CBP strongly-dependent group 1 enhancer GRCh37_chr2:210782411-210783610 [Gene]
UNC80:unc-80 homolog, NALCN channel complex subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q34

Genomic location:

Preferred name:

NM_001371986.1(UNC80):c.5296C>T (p.Pro1766Ser)

HGVS:

NC_000002.12:g.209918616C>T
NG_051361.1:g.151692C>T
NM_001371986.1:c.5296C>TMANE SELECT
NM_032504.2:c.5098C>T
NM_182587.4:c.5083C>T
NP_001358915.1:p.Pro1766Ser
NP_115893.1:p.Pro1700Ser
NP_115893.1:p.Pro1700Ser
NP_872393.3:p.Pro1695Ser
NC_000002.11:g.210783340C>T
NM_032504.1:c.5098C>T
Q8N2C7:p.Pro1700Ser

Protein change:

P1695S; PRO1700SER

Links:

UniProtKB: Q8N2C7#VAR_075875; OMIM: 612636.0001; dbSNP: rs869025316

NCBI 1000 Genomes Browser:

rs869025316

Molecular consequence:

NM_001371986.1:c.5296C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_032504.2:c.5098C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_182587.4:c.5083C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001987956	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 6, 2020)	germline	clinical testing	Citation Link,
SCV002135418	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26708751, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001987956

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 6, 2020)

germline

clinical testing

Citation Link,

SCV002135418

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 5, 2022)

germline

clinical testing

PubMed (2)
[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	not provided	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 Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.

Stray-Pedersen A, Cobben JM, Prescott TE, Lee S, Cang C, Aranda K, Ahmed S, Alders M, Gerstner T, Aslaksen K, Tétreault M, Qin W, Hartley T, Jhangiani SN, Muzny DM, Tarailo-Graovac M, van Karnebeek CD; Care4Rare Canada Consortium.; Baylor-Hopkins Center for Mendelian Genomics., Lupski JR, Ren D, Yoon G.

Am J Hum Genet. 2016 Jan 7;98(1):202-9. doi: 10.1016/j.ajhg.2015.11.004. Epub 2015 Dec 17.

PubMed [citation]

PMID:: 26708751
PMCID:: PMC4716670

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV001987956.2

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

Description

Published functional studies suggest this variant has a damaging effect on NALCN channel currents (Stray-Pedersen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26708751, 31589614)

#	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		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002135418.3

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

Description

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. Experimental studies have shown that this missense change affects UNC80 function (PMID: 26708751). 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 not expected to disrupt UNC80 protein function. ClinVar contains an entry for this variant (Variation ID: 222010). This missense change has been observed in individual(s) with UNC80-related conditions (PMID: 26708751). This variant is present in population databases (no rsID available, gnomAD 0.05%). This sequence change replaces proline with serine at codon 1700 of the UNC80 protein (p.Pro1700Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine.

#	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: Sep 29, 2024

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