NM_000492.4(CFTR):c.508C>T (p.Arg170Cys) AND Cystic fibrosis

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Jul 14, 2023
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:: RCV000526413.18

Allele description [Variation Report for NM_000492.4(CFTR):c.508C>T (p.Arg170Cys)]

NM_000492.4(CFTR):c.508C>T (p.Arg170Cys)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.508C>T (p.Arg170Cys)

HGVS:

NC_000007.14:g.117534294C>T
NG_016465.4:g.73511C>T
NM_000492.4:c.508C>TMANE SELECT
NP_000483.3:p.Arg170Cys
NP_000483.3:p.Arg170Cys
LRG_663t1:c.508C>T
LRG_663:g.73511C>T
LRG_663p1:p.Arg170Cys
NC_000007.13:g.117174348C>T
NM_000492.3:c.508C>T
NM_000492.4:c.508C>T
p.Arg170Cys

Protein change:

R170C

Links:

dbSNP: rs578029902

NCBI 1000 Genomes Browser:

rs578029902

Molecular consequence:

NM_000492.4:c.508C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

Recent activity

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BP731210 Osada Taira anterior neuroectoderm (ANE) pCS105 cDNA library Xenopus la...
BP731210 Osada Taira anterior neuroectoderm (ANE) pCS105 cDNA library Xenopus laevis cDNA clone XL483j20ex 3', mRNA sequence
gi|46079803|gnl|dbEST|24596943|dbj| 210.1|

Nucleotide
JGI_XZG17008.fwd NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7533173 5'...
JGI_XZG17008.fwd NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7533173 5', mRNA sequence
gi|73753433|gnl|dbEST|31014648|gb|C 48.2|

Nucleotide
EC0CBA004CD02.b1 Xenopus tropicalis xtbs plasmid library Xenopus tropicalis cDNA...
EC0CBA004CD02.b1 Xenopus tropicalis xtbs plasmid library Xenopus tropicalis cDNA clone xtbs04H03 3', mRNA sequence
gi|45850152|gnl|dbEST|22182332|gb|C 95.1|

Nucleotide
dab76e07.x1 NICHD_XGC_Emb4 Xenopus laevis cDNA clone IMAGE:4202988 3', mRNA sequ...
dab76e07.x1 NICHD_XGC_Emb4 Xenopus laevis cDNA clone IMAGE:4202988 3', mRNA sequence
gi|13594817|gnl|dbEST|8304751|gb|BG 3.1|

Nucleotide
da89f11.y1 Xenopus laevis tadpole stage 24 Xenopus laevis cDNA 5' similar to TR:...
da89f11.y1 Xenopus laevis tadpole stage 24 Xenopus laevis cDNA 5' similar to TR:O22416 O22416 TUBULIN UNI3, mRNA sequence
gi|7697287|gnl|dbEST|4226370|gb|AW7 .1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000625754	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 17, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14526128, 15097853, 15126740, 24958810, 16189704, 16617247, 21520337, 28492532
SCV000792509	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 28, 2017)	unknown	clinical testing	Citation Link,
SCV001185415	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 6, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14526128, 15097853, 16488363, 19812525, 24958810, 34860163 Citation Link,
SCV002027357	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004024548	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 14, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14526128, 15126740, 24958810, 28366727, 28544683, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples.

McGinniss MJ, Chen C, Redman JB, Buller A, Quan F, Peng M, Giusti R, Hantash FM, Huang D, Sun W, Strom CM.

Hum Genet. 2005 Dec;118(3-4):331-8. Epub 2005 Sep 28.

PubMed [citation]

PMID:: 16189704

Cystic Fibrosis testing among Arab-Americans.

Wei S, Feldman GL, Monaghan KG.

Genet Med. 2006 Apr;8(4):255-8.

PubMed [citation]

PMID:: 16617247

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625754.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the CFTR protein (p.Arg170Cys). This variant is present in population databases (rs578029902, gnomAD 0.02%). This missense change has been observed in individual(s) with alcohol-related pancreatitis and congenital absence of the vas deferens (PMID: 14526128, 15097853, 15126740, 24958810). ClinVar contains an entry for this variant (Variation ID: 455782). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg170 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 16189704, 16617247, 21520337), which suggests that this may be a clinically significant amino acid residue. 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.

#	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 Counsyl, SCV000792509.1

#	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 Ambry Genetics, SCV001185415.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.R170C variant (also known as c.508C>T), located in coding exon 5 of the CFTR gene, results from a C to T substitution at nucleotide position 508. The arginine at codon 170 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in an individual with alcohol related pancreatitis in conjunction with p.F508del (Bernardino AL et al. JOP, 2003 Sep;4:169-77). This variant was also identified in one individual with alcohol related pancreatitis and infertility and one individual diagnosed with congenital absence of the vas deferens (Casals T et al. Pancreas, 2004 May;28:374-9; Sharma H et al. Mol. Hum. Reprod., 2014 Sep;20:827-35). In addition, this variant was identified in a control individual (Le Marechal et al. Hum Genet. 2001 Apr;108(4):290-8). This alteration was also identified in an individual diagnosed with cystic fibrosis however further details were not provided (Erdoan M et al. Balkan Med J, 2021 Nov;38:357-364). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.

#	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 Genome-Nilou Lab, SCV002027357.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV004024548.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This CFTR missense variant has been identified in individuals features of cystic fibrosis but not a classic cystic fibrosis phenotype. This variant (rs578029902) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 13/ 250410 total alleles; 0.005%; no homozygotes) and has been reported in ClinVar (Variation ID: 455782). Two bioinformatic tools queried predict that this substitution would be damaging and the arginine residue at this position is evolutionarily conserved across most species assessed. We consider the clinical significance of CFTR c.508C>T to be uncertain at this time.

#	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: Oct 13, 2024

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