VCV002154293.3 - ClinVar

NM_005477.3(HCN4):c.3488C>T (p.Pro1163Leu)

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.

(2)

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_005477.3(HCN4):c.3488C>T (p.Pro1163Leu)

Variation ID: 2154293 Accession: VCV002154293.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q24.1 15: 73322605 (GRCh38) [ NCBI UCSC ] 15: 73614946 (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	Feb 8, 2023	Jul 23, 2024	Jul 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005477.3:c.3488C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005468.1:p.Pro1163Leu	missense
NM_005477.2:c.3488C>T
NC_000015.10:g.73322605G>A
NC_000015.9:g.73614946G>A
NG_009063.1:g.51660C>T

... more HGVS ... less HGVS

Protein change

P1163L

Other names

Canonical SPDI

NC_000015.10:73322604:G:A

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.

Links

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.
HCN4		-	-	GRCh38 GRCh37	1589	1772

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.
Brugada syndrome 8	Uncertain significance (1)	criteria provided, single submitter	May 13, 2023	RCV003081713.3
Sick sinus syndrome 2, autosomal dominant	Uncertain significance (1)	criteria provided, single submitter	Jul 16, 2023	RCV004594667.1

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 (May 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Brugada syndrome 8 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003466913.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Comment: 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 … (more) 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. 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 HCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 2154293). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1163 of the HCN4 protein (p.Pro1163Leu). (less)
Uncertain significance (Jul 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sick sinus syndrome 2, autosomal dominant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086954.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 28182231 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with sick sinus syndrome 2 (MIM#163800). Gain of function has also been reported, associated with inappropriate sinus tachycardia (PMID: 28182231). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 20 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Pro1163His) and p.(Pro1163Thr) have been reported as VUS by clinical diagnostic laboratories (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

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. 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 HCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 2154293). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1163 of the HCN4 protein (p.Pro1163Leu).

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with sick sinus syndrome 2 (MIM#163800). Gain of function has also been reported, associated with inappropriate sinus tachycardia (PMID: 28182231). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 20 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Pro1163His) and p.(Pro1163Thr) have been reported as VUS by clinical diagnostic laboratories (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial Inappropriate Sinus Tachycardia.	Baruscotti M	European heart journal	2017	PMID: 28182231

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_005477.3(HCN4):c.3488C>T (p.Pro1163Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...