NM_001127222.2(CACNA1A):c.6505C>T (p.Arg2169Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 20, 2020
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:: RCV000732133.19

Allele description [Variation Report for NM_001127222.2(CACNA1A):c.6505C>T (p.Arg2169Cys)]

NM_001127222.2(CACNA1A):c.6505C>T (p.Arg2169Cys)

Gene:

CACNA1A:calcium voltage-gated channel subunit alpha1 A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_001127222.2(CACNA1A):c.6505C>T (p.Arg2169Cys)

HGVS:

NC_000019.10:g.13209333G>A
NG_011569.1:g.302128C>T
NM_000068.4:c.6523C>T
NM_001127221.2:c.6508C>T
NM_001127222.1:c.6505C>T
NM_001127222.2:c.6505C>TMANE SELECT
NM_001174080.2:c.6514C>T
NM_023035.3:c.6523C>T
NP_000059.3:p.Arg2175Cys
NP_001120693.1:p.Arg2170Cys
NP_001120693.1:p.Arg2170Cys
NP_001120694.1:p.Arg2169Cys
NP_001167551.1:p.Arg2172Cys
NP_075461.2:p.Arg2175Cys
LRG_7t1:c.6508C>T
LRG_7:g.302128C>T
LRG_7p1:p.Arg2170Cys
NC_000019.9:g.13320147G>A
NM_000068.2:c.6508C>T
NM_001127221.1:c.6508C>T

Protein change:

R2169C

Links:

dbSNP: rs375354077

NCBI 1000 Genomes Browser:

rs375354077

Molecular consequence:

NM_000068.4:c.6523C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127221.2:c.6508C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127222.2:c.6505C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001174080.2:c.6514C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_023035.3:c.6523C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000571342	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Aug 15, 2016)	germline	clinical testing	Citation Link,
SCV000860043	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Mar 22, 2018)	germline	clinical testing	Citation Link,
SCV001143345	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely benign (Apr 20, 2020)	unknown	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

SCV000571342

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Aug 15, 2016)

germline

clinical testing

Citation Link,

SCV000860043

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL ClinVar v180209 classification definitions)

Uncertain significance
(Mar 22, 2018)

germline

clinical testing

Citation Link,

SCV001143345

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely benign
(Apr 20, 2020)

unknown

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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000571342.4

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

Description

A variant of uncertain significance has been identified in the CACNA1A gene. The R2170C variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although theR2170C was not observed with any significant frequency in approximately 6,000 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, the data was noted to have reduced depth of sequencingreads and therefore may be unreliable. The R2170C variant is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant isprobably damaging to the protein structure/function. However, missense variants in nearby residues have not beenreported in the Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al.,2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenicvariant 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 Eurofins Ntd Llc (ga), SCV000860043.1

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

From Athena Diagnostics, SCV001143345.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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