NM_001371986.1(UNC80):c.1806G>C (p.Gln602His) AND Hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 2, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000258922.10

Allele description [Variation Report for NM_001371986.1(UNC80):c.1806G>C (p.Gln602His)]

NM_001371986.1(UNC80):c.1806G>C (p.Gln602His)

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.1806G>C (p.Gln602His)

HGVS:

NC_000002.12:g.209819105G>C
NG_051361.1:g.52181G>C
NM_001371986.1:c.1806G>CMANE SELECT
NM_032504.2:c.1806G>C
NM_182587.4:c.1806G>C
NP_001358915.1:p.Gln602His
NP_115893.1:p.Gln602His
NP_115893.1:p.Gln602His
NP_872393.3:p.Gln602His
NC_000002.11:g.210683829G>C
NM_032504.1:c.1806G>C
NM_032504.2:c.1806G>C

Protein change:

Q602H

Links:

dbSNP: rs200473652

NCBI 1000 Genomes Browser:

rs200473652

Molecular consequence:

NM_001371986.1:c.1806G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_032504.2:c.1806G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_182587.4:c.1806G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (IHPRF2)
Identifiers:: MONDO: MONDO:0014777; MedGen: C4225203; Orphanet: 371364; OMIM: 616801

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000328693	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (HA_assertions_20161101)	Likely pathogenic (Oct 13, 2016)	paternal	research	Citation Link,
SCV001136157	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002768725	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Sep 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003828044	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 23, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	paternal	yes	1	not provided	not provided	1	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000328693.3

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

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

From Mendelics, SCV001136157.1

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768725.1

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

Description

A heterozygous missense variant, NM_032504.1(UNC80):c.1806G>C, has been identified in exon 12 of 64 of the UNC80 gene. The variant is predicted to result in a minor amino acid change from glutamine to histidine at position 602 of the protein (NP_115893.1(UNC80):p.(Gln602His)). The glutamine residue at this position has high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.14% (271 heterozygotes, 1 homozygote). The variant has been previously described as likely pathogenic (ClinVar, Decipher) and also VUS (EGL Genetics). Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN.

#	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

From Revvity Omics, Revvity, SCV003828044.2

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

#	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: Nov 24, 2024

ClinVar

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