NM_005477.3(HCN4):c.3497_3500del (p.Ser1166fs) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 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:: RCV000767026.2

Allele description [Variation Report for NM_005477.3(HCN4):c.3497_3500del (p.Ser1166fs)]

NM_005477.3(HCN4):c.3497_3500del (p.Ser1166fs)

Gene:

HCN4:hyperpolarization activated cyclic nucleotide gated potassium channel 4 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

15q24.1

Genomic location:

Preferred name:

NM_005477.3(HCN4):c.3497_3500del (p.Ser1166fs)

HGVS:

NC_000015.10:g.73322594_73322597del
NC_000015.9:g.73614934_73614937del
NG_009063.1:g.51669_51672del
NM_005477.3:c.3497_3500delMANE SELECT
NP_005468.1:p.Ser1166fs
NC_000015.9:g.73614934_73614937del
NC_000015.9:g.73614934_73614937delAAAG
NC_000015.9:g.73614935_73614938del
NM_005477.2:c.3497_3500del
NM_005477.2:c.3497_3500delCTTT
p.S1166CfsX14
p.Ser1166CysfsX14

Protein change:

S1166fs

Links:

dbSNP: rs774674047

NCBI 1000 Genomes Browser:

rs774674047

Molecular consequence:

NM_005477.3:c.3497_3500del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000223504	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Sep 21, 2016)	germline	clinical testing	Citation Link,
SCV002502322	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000223504

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Sep 21, 2016)

germline

clinical testing

Citation Link,

SCV002502322

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 5, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	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 GeneDx, SCV000223504.14

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

Description

The c.3497_c.3500delCTTT variant in the HCN4 gene has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. This variant causes a shift in reading frame starting at codon Serine 1166, changing it to a Cysteine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Ser1166CysfsX14. This variant is expected to result in an abnormal, truncated protein product. However, the majority of mutations in HCN4 are missense changes indicating haploinsufficiency of HCN4 may not be sufficient to cause an arrhythmia phenotype. With the information available at this time, we cannot definitively determine if c.3497_c.3500delCTTT is a disease-causing mutation or a rare benign variant.

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002502322.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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