ClinVar Miner

Submissions for variant NM_000342.3(SLC4A1):c.118G>A (p.Glu40Lys) (rs45562031)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000247655 SCV000303728 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000298897 SCV000403310 benign Hemolytic anemia 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Bioinformatics dept.,Datar Cancer Genetics Limited, India RCV000494697 SCV000579503 likely pathogenic Cryohydrocytosis 2017-06-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000512811 SCV000605168 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512811 SCV000608818 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
Mendelics RCV000019333 SCV001140661 uncertain significance Spherocytosis type 4 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000019333 SCV001280761 benign Spherocytosis type 4 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001127848 SCV001287204 benign Autosomal dominant distal renal tubular acidosis 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000019333 SCV001338133 likely benign Spherocytosis type 4 2020-06-01 criteria provided, single submitter clinical testing The SLC4A1 c.118G>A; p.Glu40Lys variant (rs45562031), also known as Band 3 Montefiore, is reported in the literature as a homozygous variant in one individual affected with hemolytic anemia with concomitant reduction in protein 4.2 (EPB42) (Rybicki 1993). However, heterozygous carrier relatives of this individual did not presented with any decrease in protein 4.2 (Rybicki 1993). In vitro functional analyses suggest this variant may be associated with reduced binding of Band 3 and Protein 4.2 (Bustos 2011). This variant also has conflicting reports of pathogenicity in ClinVar (Variation ID: 17756). This variant is found in the general population with an overall allele frequency of 1.1% (3,038/282,752 alleles, including 17 homozygotes) in the Genome Aggregation Database, which is significantly higher than the incidence of spherocytosis in the general population. The glutamic acid at codon 40 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on limited clinical reports and the abundance of this variant in the general population, this variant is considered to be likely benign.
Broad Institute Rare Disease Group, Broad Institute RCV000019333 SCV001435127 likely benign Spherocytosis type 4 criteria provided, single submitter research The homozygous p.Glu40Lys variant in SLC4A1 has been identified in an individual with a previous splenectomy (PMID: 8471774), but has been identified in >1% of European (non-Finnish) chromosomes and 3 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive spherocytosis.
Institute of Human Genetics, University of Leipzig Medical Center RCV001127848 SCV001440848 uncertain significance Autosomal dominant distal renal tubular acidosis 2019-01-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000512811 SCV001712919 uncertain significance not provided 2021-01-26 criteria provided, single submitter clinical testing
Invitae RCV000512811 SCV001723472 benign not provided 2020-12-05 criteria provided, single submitter clinical testing
GeneDx RCV000512811 SCV001860130 benign not provided 2020-03-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 33226606, 31723846, 27535533, 27354418, 21039340, 16411779, 9207478, 8471774, 20981092)
OMIM RCV000019333 SCV000039623 pathogenic Spherocytosis type 4 1993-04-15 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000512811 SCV001552567 likely benign not provided no assertion criteria provided clinical testing The SLC4A1 p.Glu40Lys variant was identified in the literature in a female with episodic hemolytic anemia that was homozygous for the p.E40K variant (Rybicki_1993_8471774). The variant was identified in dbSNP (ID: rs45562031), LOVD 3.0 and ClinVar (classified as likely benign by PreventionGenetics and Illumina, as likely pathogenic by Bioinformatics dept., Datar Cancer Genetics Limited, India and as uncertain signifiicance by ARUP Laboratories and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 3038 of 282752 chromosomes (17 homozygous) at a frequency of 0.010744 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2337 of 129084 chromosomes (freq: 0.0181), Other in 90 of 7228 chromosomes (freq: 0.01245), European (Finnish) in 234 of 25114 chromosomes (freq: 0.009318), Latino in 231 of 35438 chromosomes (freq: 0.006518), African in 74 of 24954 chromosomes (freq: 0.002965), South Asian in 63 of 30616 chromosomes (freq: 0.002058) and Ashkenazi Jewish in 9 of 10368 chromosomes (freq: 0.000868), but was not observed in the East Asian population. The p.Glu40 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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