ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.131C>A (p.Ala44Asp)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003086326 SCV004242283 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2024-01-23 reviewed by expert panel curation The c.131C>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Alanine by Aspartic Acid at amino acid 44 (p.Ala44Asp). The filtering allele frequency (the upper threshold of the 95% CI of 36/1177718) of the c.131C>A variant in DCLRE1C is 0.00002087 for European (non-Finnish) chromosomes by gnomAD v.4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1.0).
Labcorp Genetics (formerly Invitae), Labcorp RCV003086326 SCV003478321 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 44 of the DCLRE1C protein (p.Ala44Asp). This variant is present in population databases (rs770015010, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV003269441 SCV003947174 uncertain significance Inborn genetic diseases 2023-04-20 criteria provided, single submitter clinical testing The c.131C>A (p.A44D) alteration is located in exon 2 (coding exon 2) of the DCLRE1C gene. This alteration results from a C to A substitution at nucleotide position 131, causing the alanine (A) at amino acid position 44 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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