ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.

This missense variant also known as Band 3 Montefiore occurs in an acidic region of the N-terminus that contains binding sites for aldolase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, denatured hemoglobins, and protein 4.2 (PMID:11049968). Functional studies indicate the alteration results in impaired binding to protein 4.2. Introduction of a positive charge by the E40K mutants may serve to disrupt the acidic protein 4.2-binding surface on cdAE1 (PMID:21039340). In a single case report, this mutation was detected in the homozygous state in a patient reported to have moderate and episodic nonimmune hemolytic anemia coincident with pregnancy and splenomegaly, spherocytosis, and increased osmotic fragility with a 88% decrease in protein 4.2. None of the heterozygous relatives were symptomatic and had a normal RBC membrane protein 4.2 content (PMID:8471774). This alteration is common in Europeans (MAF 1.8%) but is found at low frequencies in almost all other populations in gnomAD. Due to insufficient data available to clearly classify this variant as pathogenic or benign, it is categorized as a variant of uncertain significance.

This variant is associated with the following publications: (PMID: 33226606, 31723846, 27535533, 27354418, 21039340, 16411779, 9207478, 8471774, 20981092)

SLC4A1: BP4, BS1, BS2

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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.