Submissions for variant NM_000388.4(CASR):c.220A>C (p.Met74Leu)

gnomAD frequency: 0.00002  dbSNP: rs745377913

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555584	SCV000638038	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 74 of the CASR protein (p.Met74Leu). This variant is present in population databases (rs745377913, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of hypocalciuric hypercalcemia and/or hyperparathyroidism (internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 606,512 individuals referred to our laboratory for CASR testing. ClinVar contains an entry for this variant (Variation ID: 463920). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CASR function (PMID: 32386559). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000711034	SCV000841354	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000711034	SCV002520154	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with slightly elevated serum calcium levels (Dershem et al., 2020); Published functional studies demonstrate reduced protein expression and plasma membrane localization/signaling (Dershem et al., 2020); This variant is associated with the following publications: (PMID: Antony_2021_Abstract, 32386559)
Ambry Genetics	RCV004023947	SCV002729581	uncertain significance	Nephrolithiasis/nephrocalcinosis	2024-02-07	criteria provided, single submitter	clinical testing	The p.M74L variant (also known as c.220A>C), located in coding exon 2 of the CASR gene, results from an A to C substitution at nucleotide position 220. The methionine at codon 74 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506333	SCV002816497	uncertain significance	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2022-04-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554801	SCV004105575	uncertain significance	CASR-related disorder	2023-08-15	criteria provided, single submitter	clinical testing	The CASR c.220A>C variant is predicted to result in the amino acid substitution p.Met74Leu. This variant was reported in an individual with elevated serum calcium levels, and in vitro experimental studies suggested this variant impacts protein function (Dershem et al 2020. PubMed ID: 32386559). This variant is reported in 0.0026% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-121975962-A-C). An alternative nucleotide change affected the same amino acid (p.Met74Val) has been reported in individuals with hypercalcemia (Vargas-Poussou et al. 2016. PubMed ID: 26963950; Mouly et al. 2020. PubMed ID: 32347971 ). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403288	SCV004121717	uncertain significance	not specified	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: CASR c.220A>C (p.Met74Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.220A>C has been reported in the literature in an individual with mildly increased serum calcium levels (Dershem_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Dershem_2020), finding reduced expression of the mature protein and reduced plasma membrane localization. The following publication has been ascertained in the context of this evaluation (PMID: 32386559). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000711034	SCV005410369	uncertain significance	not provided	2023-11-15	criteria provided, single submitter	clinical testing	PP2, PM2, PS4_moderate