7-117540305-C-A

Variant names:

• chr7-117540305-C-A
• rs76879328
• NM_000492.4:c.1075C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000492.4(CFTR):​c.1075C>A​(p.Gln359Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.43

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 7-117540305-C-A is Pathogenic according to our data. Variant chr7-117540305-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7169.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}. Variant chr7-117540305-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1075C>A	p.Gln359Lys	missense_variant	Exon 8 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1075C>A	p.Gln359Lys	missense_variant	Exon 8 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000592 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1

Oct 05, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.[(Q359K;T360K)] variant (also known as c.[1075C>A;1079C>A]), located in coding exon 8 of the CFTR gene, is the result of two separate variants, p.Q359K (c.1075C>A) and p.T360K (c.1079C>A), being detected in cis. The glutamine at codon 359 and the threonine at codon 360 are both replaced by lysine, an amino acid with similar properties. The p.[(Q359K;T360K)] variant was detected in the homozygous state in patients affected with cystic fibrosis from three unrelated Georgian Jewish families (Shoshani T et al. Genomics. 1993;15(1):236-7). The p.Q359K and p.T360K variants were previously reported in the SNPDatabase as rs76879328 and rs75053309, respectively. These variants were not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, these variants were not observed in 6503 samples (13006 alleles) with coverage at this position. The glutamine at codon 359 is highly conserved in available vertebrate species, and the p.Q359K alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. The threonine at codon 360 is not well conserved in available vertebrate species, and the p.T360K alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, the p.[(Q359K;T360K)] variant is likely to be pathogenic. -

Hereditary pancreatitis Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Feb 23, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1075C>A (p.Gln359Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251054 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.1075C>A has not been reported in isolation in literature among individuals affected with Cystic Fibrosis. It has however been observed as part of a multinucleotide variation, that is variably annotated either as Q359K/T360K, p.[Gln359Lys;Thr360Lys], c.[1075C>A;1079C>A], or c.1075_1079delCAAACinsAAAAA or p.Gln359_Thr360delinsLysLys (example, Shoshani_1993, Wilschanski_1999, Bobadilla_2002, Sugarman_2004, Heim_2004, Chevalier-Porst_1994, Heim_2001, Petreska_1998, Schrijver_2005, Sosnay_2013, Castellani_2008, Petrova_2020). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect in isolation (Sosnay_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant in isolation was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.9	M;.;.;.;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N;.;.;N;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.011	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.88
MutPred		0.67		Gain of ubiquitination at Q359 (P = 0.0289);Gain of ubiquitination at Q359 (P = 0.0289);Gain of ubiquitination at Q359 (P = 0.0289);.;Gain of ubiquitination at Q359 (P = 0.0289);
MVP		1.0
MPC		0.0048
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.58
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76879328; hg19: chr7-117180359;