VCV000005973.13 - ClinVar

NM_020806.5(GPHN):c.28A>T (p.Asn10Tyr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020806.5(GPHN):c.28A>T (p.Asn10Tyr)

Variation ID: 5973 Accession: VCV000005973.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q23.3 14: 66508555 (GRCh38) [ NCBI UCSC ] 14: 66975273 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	May 12, 2024	Nov 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_020806.5:c.28A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065857.1:p.Asn10Tyr	missense
NM_001024218.2:c.28A>T	NP_001019389.1:p.Asn10Tyr	missense
NM_001377514.1:c.28A>T	NP_001364443.1:p.Asn10Tyr	missense
NM_001377515.1:c.28A>T	NP_001364444.1:p.Asn10Tyr	missense
NM_001377516.1:c.28A>T	NP_001364445.1:p.Asn10Tyr	missense
NM_001377517.1:c.28A>T	NP_001364446.1:p.Asn10Tyr	missense
NM_001377518.1:c.28A>T	NP_001364447.1:p.Asn10Tyr	missense
NM_001377519.1:c.28A>T	NP_001364448.1:p.Asn10Tyr	missense
NC_000014.9:g.66508555A>T
NC_000014.8:g.66975273A>T
NG_008875.1:g.6149A>T
	Q9NQX3:p.Asn10Tyr

... more HGVS ... less HGVS

Protein change

N10Y

Other names

A28T

Canonical SPDI

NC_000014.9:66508554:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00015

The Genome Aggregation Database (gnomAD) 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00017

The Genome Aggregation Database (gnomAD), exomes 0.00019

Links

OMIM: 603930.0002 dbSNP: rs121908539 ClinGen: CA253669 UniProtKB: Q9NQX3#VAR_044162 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GPHN		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	757	1933

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyperekplexia	Uncertain significance (1)	no assertion criteria provided	Jul 4, 2003	RCV000006337.3
Hyperekplexia 1	Pathogenic (1)	no assertion criteria provided	Oct 4, 2012	RCV000031964.3
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (1)	criteria provided, single submitter	Nov 15, 2023	RCV000697829.8
Hyperekplexia 1 Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C	Uncertain significance (1)	criteria provided, single submitter	Feb 24, 2022	RCV002496282.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Sep 29, 2022	RCV003480022.1
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 11, 2021	RCV002512829.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Feb 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperekplexia 1 Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002796425.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Sep 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004227310.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 12684523 Comment: PP2, PM2 Number of individuals with the variant: 1
Uncertain significance (Nov 15, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000826460.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28492532‚ 12684523 Comment: This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 10 of the GPHN protein (p.Asn10Tyr). … (more) This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 10 of the GPHN protein (p.Asn10Tyr). This variant is present in population databases (rs121908539, gnomAD 0.03%). This missense change has been observed in individual(s) with neonatal hypertonia and hyperekplexia (PMID: 12684523). ClinVar contains an entry for this variant (Variation ID: 5973). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect GPHN function (PMID: 12684523). 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. (less)
Uncertain significance (Jun 11, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003633770.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 12684523 Comment: The c.28A>T (p.N10Y) alteration is located in exon 1 (coding exon 1) of the GPHN gene. This alteration results from a A to T substitution … (more) The c.28A>T (p.N10Y) alteration is located in exon 1 (coding exon 1) of the GPHN gene. This alteration results from a A to T substitution at nucleotide position 28, causing the asparagine (N) at amino acid position 10 to be replaced by a tyrosine (Y). This alteration was detected in a heterozygous patient presenting with neonatal hypertonia and excessive startle response. However, this patient was found at age four to have transient recovery of phenotype with no features of molybdenum metabolism disruption (Rees, 2003). The in silico prediction for the p.N10Y alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jul 04, 2003)	no assertion criteria provided Method: literature only	VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026519.2 First in ClinVar: Apr 04, 2013 Last updated: May 12, 2024	Publications: PubMed (1) PubMed: 12684523 Comment on evidence: This variant is classified as a variant of unknown significance because its contribution to hyperekplexia has not been confirmed. In 1 of 38 unrelated patients … (more) This variant is classified as a variant of unknown significance because its contribution to hyperekplexia has not been confirmed. In 1 of 38 unrelated patients with hyperekplexia (see 149400), Rees et al. (2003) detected a heterozygous 28A-T transversion in exon 1 of the GPHN gene, resulting in an asn10-to-tyr (N10Y) substitution at the extreme N terminus. The N10Y variant was not found in 94 controls. The GPHN gene was chosen for sequencing after it was shown to interact with the GLRB (138492) subunit. The N10Y substitution is located 5 residues upstream from a putative region important for protein interactions; however, in vitro functional expression studies in HEK293 cells suggested that the variant did not affect the structural lattices formed by gephyrin or interrupt its interactions with GLRB. The variant protein did not interrupt cell surface clustering. Thus, the functional effect of the variant remained elusive. (less)
pathologic (Oct 04, 2012)	no assertion criteria provided Method: curation	Hyperekplexia Affected status: not provided Allele origin: not provided	GeneReviews Accession: SCV000054656.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2013	Comment: Converted during submission to Pathogenic.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 10 of the GPHN protein (p.Asn10Tyr). This variant is present in population databases (rs121908539, gnomAD 0.03%). This missense change has been observed in individual(s) with neonatal hypertonia and hyperekplexia (PMID: 12684523). ClinVar contains an entry for this variant (Variation ID: 5973). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect GPHN function (PMID: 12684523). 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.

Comment:

The c.28A>T (p.N10Y) alteration is located in exon 1 (coding exon 1) of the GPHN gene. This alteration results from a A to T substitution at nucleotide position 28, causing the asparagine (N) at amino acid position 10 to be replaced by a tyrosine (Y). This alteration was detected in a heterozygous patient presenting with neonatal hypertonia and excessive startle response. However, this patient was found at age four to have transient recovery of phenotype with no features of molybdenum metabolism disruption (Rees, 2003). The in silico prediction for the p.N10Y alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hereditary Hyperekplexia Overview.	Adam MP	-	2019	PMID: 20301437
Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia.	Rees MI	The Journal of biological chemistry	2003	PMID: 12684523

Text-mined citations for rs121908539 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_020806.5(GPHN):c.28A>T (p.Asn10Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908539 ...